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Erschienen in: European Surgery 3/2017

Open Access 01.06.2017 | original article

Oxidative stress and angiogenesis in primary hyperparathyroidism

verfasst von: Mariusz Deska, Ewa Romuk, Oliwia Anna Segiet, Grzegorz Buła, Witold Truchanowski, Dominika Stolecka, Ewa Birkner, Jacek Gawrychowski

Erschienen in: European Surgery | Ausgabe 3/2017

Summary

Background

The inappropriate elevation of parathormone (PTH), which regulates the process of angiogenesis in parathyroid tissue, causes the changes of activity of enzymes responsible for the removal of free radicals. Parathyroidectomy (PTX) in patients with primary hyperparathyroidism (PHPT) lowers the level of PTH and leads to the reduction of risk of cardiovascular and all-cause mortality by normalization of the antioxidant status. Therefore, the aims of the study were to assess the activity of antioxidant enzymes and free radical reaction products in patients after parathyroidectomy, and to evaluate the correlation between the systemic oxidative stress and angiogenic parameters.

Materials and methods

Patients with PHPT treated surgically were enrolled into the study. Total antioxidant capacity (TAC), total oxidative status (TOS), oxidative stress index (OSI), superoxide dismutase (SOD), ceruloplasmin (CER), lipid hydroperoxides (LHP) and malondialdehyde (MDA) were measured before and after parathyroidectomy. The immunohistological expression of angiogenic factors in parathyroid specimens was assessed by the BrightVision method from ImmunoLogic using murine monoclonal anti-human: anti-VEGF, anti-CD31 and anti-CD106 antibodies.

Results

The significant increase of TAC, CER, reduction of TOS, MDA, SOD, especially for cytoplasmic form, and significant decrease of OSI, LHP were observed after PTX. There was no significant correlation between changes of oxidative stress markers and angiogenic parameters: VEGF, CD-31, CD-106 in parathyroid tissue. The correlation level was low and medium.

Conclusions

Parathyroidectomy causes down-regulation of lipid peroxidation processes and leads to reduction of oxidative stress in patients with PHPT. The decrease in the OSI is the results of down-regulation of oxidative stress in the postoperative period. The change of the antioxidant status has no impact on angiogenesis processes in parathyroid tissue.

Introduction

Primary hyperparathyroidism (PHPT) is caused by an inappropriate elevation of parathormone (PTH) level by one or more glands, which usually results in hypercalcemia [1]. Its prevalence has been estimated to be 0.1–0.3% in the general population and is more common in women than in men [2]. Excessive secretion of PTH directly stimulates bone resorption, increases calcium absorption in the intestine, inhibits the secretion of calcium by the kidney, indirectly enhances the production of vitamin D, which promotes calcium absorption in the intestine. Due to the results of studies revealing the impact of PHPT on the increase of the incidence of cardiovascular diseases, and probably also cancers, in patients with PHPT we should use surgical treatment [35]. Patients with primary hyperparathyroidism have increased risk of cardiovascular disease, which may be caused by a great number of factors, such as hypercalcemia [6], low vitamin D level [7], osteoporosis [8], or hyperphosphatemia [9]. Several studies demonstrated that oxidative stress also contributed to the development of vascular disorders [10]. Moreover, circulating oxidized plasma proteins, known as advanced oxidation protein products, play a role in the pathogenesis of chronic renal failure [11]. Endothelium is responsible for vascular tone, mainly due to the production of nitrogen monoxide (NO), which has been implicated in maintaining the balance between vasoconstriction and vasodilation. Vascular endothelial cells in diseases, including hypertension, hypercholesterolemia, and diabetes, produce increased amounts of reactive oxygen species (ROS), which cause formation of peroxynitrites and therefore neutralize NO activity. This leads to atherotrombosis and atherosclerosis [12]. Several reports suggested the possibility that parathyroidectomy could reduce the risk of cardiovascular complications [3].
The lack of calcium and phosphate homeostasis affects the functioning of the body’s defense mechanisms, eliminating free radicals, and thereby contributes to the abnormal cell oxidative profile [13]. The imbalance between the intensity of oxidation processes, which induce the formation of ROS, and antioxidative defense mechanisms is called oxidative stress. Parameters used to assess te oxidative stress are total oxidative status (TOS), total antioxidant capacity (TAC), and the oxidative stress index (OSI). Total oxidative status (TOS) is a parameter, which determines the total oxidant properties, whereas total antioxidant capacity (TAC) gives information about the antioxidant potential of body fluids in the organism, and is determined as the moles of oxidants neutralized by one liter of solution. OSI is defined as the ratio of the TOS level to TAC level [14]. One of the main consequences of ROS production is lipid oxidation, which has been implicated in the pathogenesis of many diseases. Lipids are oxidized in vivo by several different oxidants to give diverse products, in general lipid hydroperoxides (LHP) as the major primary product. One of the decay products is malondialdehyde (MDA), whose concentration increases due to enhanced production of ROS; therefore MDA is a lipid peroxidation marker used to assess lipid peroxidation caused by increased oxidative stress [15].
Reactive oxygen species can cause the oxidation of fats, proteins, DNA, and subsequently contribute to the damage of tissues. Toxic oxidation reaction products have cytostatic effect due to the cell membranes damage, and lead to cell death by apoptosis or necrosis. To avoid the mentioned consequences, in the body there are substances, acting as antioxidants, which inactivate and remove ROS. The balance is maintained by the antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase or non-enzymatic compounds, such as vitamins A, C, and E, bilirubin, albumin, uric acid, and ceruloplasmin. Ceruloplasmin (CER) is an antioxidant, which is responsible for scavenging ROS such as singlet, superoxide, and hydroxyl radicals. This glycoprotein has been implicated in copper transport, iron turnover, ferroxidase, glutathione peroxidase, and ascorbate oxidase activities. Its expression has been demonstrated in the liver, spleen, lung, testis, and brain [16]. Sulfhydryl (SH) groups, also known as thiol or sulphur groups, play a huge role in destruction of free peroxidized fatty acids and hydrogen peroxide. Glutathione (GSH) is a tripeptide with SH group, and a cosubstrate for the peroxidation inhibiting protein, which causes decomposition of hydroperoxide fatty acids located in phospholipids [17]. Sulfhydryl groups are particularly susceptible to the effects of free radicals. Several researches indicated that the assessment of the thiol groups was a better indicator of oxidative stress than the measurement of the total oxidative status (TOS) or total antioxidant capacity (TAC) [18]. In most biological processes, superoxide anion is the first generated ROS, which results in the formation of subsequent ROS. Superoxide dismutase (SOD) is an ubiquitous enzyme, constituting the first line of defense, which catalyzes the conversion of superoxide anion into hydrogen peroxide and oxygen. There are four families of SOD, defined by their metal ion binding partners: Fe, Mn, Ni, or both Cu and Zn. CuZnSOD is a copper and zinc-containing homodimer that is found almost exclusively in intracellular cytoplasmic spaces. Mn-SOD exists as a tetramer and is initially synthesized with a leader peptide, which targets this manganese-containing enzyme exclusively to the mitochondrial spaces. EC-SOD is the most recently characterized SOD, exists as a copper and zinc-containing tetramer, and is synthesized with a signal peptide that directs this enzyme to extracellular spaces [19]. The enzymes decomposing hydrogen peroxide are catalase (CT) [20] and glutathione peroxidase (GPx) [21]. Another role of GPx in defense against ROS is to catalyze the coupling reaction of products of lipid peroxidation with glutathione aldehyde. By measuring the activity of the antioxidant system we can indirectly measure free-radical activity [21].
ROS are also involved in the transmission of signals, cell differentiation, and apoptosis. They may affect the functioning of the mechanism of new cells and blood vessels formation [22]. Hypoxia is a known factor up-regulating the production of free radicals, which is also a stimulator of angiogenesis [23]. This is a multistep process of formation of new blood vessels from the pre-existing microvasculature, during which endothelial cells migrate and proliferate [23]. Physiologically, it is essential for proper development, growth, and maturation of the human body and is controlled by a balance between pro- and anti-angiogenic factors and their receptors. Neovascularization is also implicated in the pathogenesis of many diseases, particularly neoplasia [24]. Because the endocrine glands are well vascularized and the structure of the vessel facilitates the exchange of various substances, including hormones, they are a common experimental model in the study on angiogenesis. Parathyroid tissue can promote spontaneous induction of angiogenesis in vitro [25] and in vivo models in a vascular endothelial growth factor-dependent manner [26]. Autotransplanted parathyroid tissue after thyroidectomy is able to produce new blood vessels and synthesize parathormone, which is responsible for maintaining calcium homeostasis [27]. Several studies demonstrated that also cultured parathyroid cells could trigger angiogenesis [26]. The strongest regulator of normal and pathological angiogenesis is vascular endothelial growth factor (VEGF). Vascular endothelial growth factor, also known as vascular permeability factor (VPF), plays a huge role in angiogenesis during embryogenesis, skeletal growth, and pathological angiogenesis associated with tumor development. Local hypoxia up-regulates VEGF synthesis [28]. Several studies confirmed its contribution to the pathogenesis of diseases, such as breast cancer, renal cell carcinoma, colorectal cancer, angiosarcoma, rheumatoid arthritis, and diabetic retinopathy [2931], Moreover, PTH regulates the expression of VEGF and metalloproteinases (MMPs) [32, 33].
Platelet endothelial cell adhesion molecule (PECAM-1), denoted cluster of differentiation 31 (CD31), is a member of type I integral membrane glycoprotein family. It is expressed on endothelial cells, peripheral lymphoid cells, platelets, monocytes, and neutrophils. CD 31 is implicated in angiogenesis, leukocyte migration, T cell activation, platelet aggregation, regulation of endothelial junctional integrity, and integrin activation [34, 35].
Vascular cell adhesion molecule-1 (VCAM-1, CD106) is present on activated vascular endothelial cells, follicular and interfollicular dentritic cells of lymph nodes, macrophages myoblasts, and bone marrow stromal cells. CD106 regulates the adhesion of lymphocytes, monocytes, eosinophils, and basophils to vascular endothelium through interaction with integrin receptors. It is also responsible for transmigration and co-stimulation of T cell proliferation [36].
The activation mechanism of angiogenesis and oxidative stress is still not completely known, but probably it remains under control because most of parathyroid tumors are benign and do not have the ability to metastasize [1, 2]. What is more, of interest is the impact of systemic oxidative stress occurring in the PHPT on the severity of angiogenesis in parathyroid tissue.
Therefore, the aims of the study were the following:
1.
Assess the activity of antioxidant enzymes and free radical reaction products in patients after parathyroidectomy;
 
2.
Evaluate the correlation between the systemic oxidative stress and angiogenic parameters.
 

Materials and methods

Blood serum and parathyroid tissue specimens, collected from 56 consecutive patients with PHPT treated surgically (age 55.66 ± 14.22 years), constituted our study material (Table 1). Blood samples for biochemical examinations were collected from patients 24 h before the surgery, as well as on postoperative day 15. At each time point, 5 ml of blood were aspirated into both vacuum tubes and vacuum tubes with an anticoagulant (EDTA). In order to obtain a hemolysate, 0.9% NaCl was added to the remaining blood cells. The material was mixed and centrifuged for 10 min at 3000 revolutions/min. Supernatant was removed and again 0.9% NaCl was added. The procedure was repeated twice. Afterward, 0.4 ml of blood was collected from the bottom of the test tube and 3.6 ml of doubly distilled water was added. After mixing, we obtained 10% blood cell lysate. The material was frozen at −80 °C. After thawing, biochemical examinations were performed.
Table 1
Group characteristics
Study group
N = 56
Mean age in years
55.6 (28–82)
Sex
Male
11 (19.6%)
Female
45 (81.4%)
Histopathology
Adenomas
36 (64.3%)
Hyperplasia
17 (30.35%)
Carcinoma
3 (5.35%)
Type of surgery
Open parathyroidectomy
56 (100%)

Biochemical analysis

Analysis of TOS and TAC

The TOS and TAC were determined in serum by the method described by Erel. TOS measurements were done by reading at end-point 560 nm in the spectrophotometer 3–4 min after mixing the samples and reagents, and the results were expressed in hydrogen peroxide liter (µmol H2O2 equiv/l). The method is based on the oxidation of ferrous ion to ferric ion in the presence of various oxidant species in acidic medium and the measurement of the ferric ion by xylenol orange [37]. TAC was assessed by the use of a standard antioxidant solution called Trolox equivalent which is analogous to vitamin E. TAC was presented as mmol Trolox equiv/l. TAC measurements were performed by kinetic reading in the spectrophotometer 5 min after the sample and reagent were mixed [38].

Analysis of OSI

After TAC and TOS measurements, the OSI levels, which allow us to make an exact comment on the oxidant and antioxidant balance, were calculated according to the following formula specified in the catalog of the kit (rel assay diagnostics): OSI = (TOS µmol/l)/(TAC [mmol Trolox equiv/l] × 100).

Analysis of antioxidants

The method of Oyanagui was used to measure the activity of superoxide dismutase (SOD) and its isoenzymes: the cytoplasmic Cu/Zn-superoxide dismutase (Cu/ZnSOD) and the mitochondrial Mn-superoxide dismutase (MnSOD). In this method, xanthine oxidase produces superoxide anions, which react with hydroxylamine forming nitric ions. This ions react with naphthalene diamine and sulfanilic acid, generating a colored product. Concentration of this product is proportional to the amount of produced superoxide anions and negatively proportional to the activity of SOD. The enzymatic activity of SOD was expressed in nitric units. The activity of SOD is equal to 1 nitric unit (NU) when it inhibits nitric ion production by 50%. Activities of SOD were normalized to milligram of protein in homogenates (NU/mg protein) [39]. The concentration of sulfhydryl groups (SH) in serum was determined by Koster method using 5,5’-dithiobis(2-nitrobenzoic acid)—DTNB. Concentration was shown in mmol/l [40]. Serum ceruloplasmin was determined spectrophotometrically using the Richterich reaction with p-phenyldiamine [41].

Analysis of lipid oxidation products

Lipid hydroperoxide concentration in serum was determined by Södergren et al. using xylene orange. Values were expressed in mmol/l. All this parameters were measured with the use of the Perkin Elmer spectrophotometer Victor X3 [42]. The malondialdehyde level was determined by the Ohkawa method using a Perkin Elmer LS45 spectrofluorometer. The concentration of MDA was expressed as mol/g of protein [43].

Immunohistochemical analysis

For immunohistology, all specimens were immediately fixed for 20 min in cold acetone (−20 °C) and immersed in embedding medium (OCT Compound, Miles Inc.), and all of them were cut serially into 5 μm thickness slides, air dried at room temperature, and assayed. Frozen sections were incubated with murine monoclonal anti-human: anti-VEGF (clone SP28), anti-CD31 (clone JC/70A), and anti-CD106 (clone 1.4C3). The dilution of the primary antibodies was 1:500 and was verified in a series of pilot experiments. The immunohistological investigations were performed by the BrightVision method from ImmunoLogic, according to the manufacturer’s instructions. The primary antibody was omitted from negative control slides. The sections were counterstained with Mayer’s hematoxylin. Each specimen was evaluated qualitatively, semiquantitatively (score index from 0 to 3+), and quantitatively. Semiquantitative score index was as follows: (0): no staining; (1+): weak focal staining; (2+): multifocal moderate staining; and (3+): diffuse strong staining. Positively stained cells were counted in all cryostat sections in at least 10 high power fields (HPF) per each biopsy under 400x magnification and averaged for each field using Nikon Eclipse 80i microscope with DSFi1 digital camera and NIS Elements software form Nikon.
All patients gave their informed consent. The protocol was approved by the institutional ethics committee.

Statistical analysis

All statistical analyses were done with the use of STATISTICA 10 program. The normality of the results distribution was verified using the Shapiro–Wilk test. Due to the small size of the groups we used non-parametric “U” Mann–Whitney test, and the data were presented as median with the first and fourth quartiles. The results were considered statistically significant if p < 0.05. The lack of statistical significance was presented as NS (nonsignificant).

Results

The activity of antioxidant enzymes and free radical reaction products in patients before and after parathyroidectomy

Parathyroidectomy in patients with PHPT resulted in the significant increase of TAC (p < 0.001) and substantial reduction of TOS (p = 0.027). Moreover, a considerable decrease in the oxidative stress index (OSI) was demonstrated (p < 0.05), which was the results of down-regulation of oxidative stress in postoperative period (Table 2). Among measured antioxidants, we observed the significant decrease in serum level of SOD (p < 0.05) mainly in cytoplasmic form CuZnSOD (p < 0.05) and the significant increase of ceruloplasmin (p < 0.05). The serum concentration of SH remained unchanged after parathyroidectomy. After surgery, we observed a significant decrease of lipid hydroperoxides (p < 0.05) and a decrease of malonic dialdehyde. Both were caused by down-regulation of ROS (Table 2). The results are presented in Fig. 1.
Table 2
The comparison of serum oxidative stress index, serum level of antioxidants, and serum lipid peroxidase products between groups before and after parathyroidectomy. Parathyroidectomy (PTX) in patients with PHPT resulted in the significant increase of TAC (p < 0.001) and substantial reduction of TOS (p = 0.027). Moreover, a considerable decrease in the oxidative stress index (OSI) was demonstrated (p < 0.05), which was the results of down-regulation of oxidative stress in postoperative period. A significant decrease in serum level of SOD (p < 0.05) mainly in cytoplasmic form CuZnSOD (p < 0.05) and the significant increase of ceruloplasmin (p < 0.05) were observed. The serum concentration of SH remained unchanged after parathyroidectomy. After surgery a significant decrease of lipid hydroperoxide (LHP, p < 0.05) and a decrease of malonic dialdehyde (MDA) were demonstrated. Both were caused by down-regulation of ROS
Measured parameters
Pre-PTX group
Post-PTX group
TAC mmol Trolox equiv/l
0.86 ± 0.15
0.95 ± 0.14*
TOS µmol H2O2 Equiv/L
5.03 ± 1.84
4.49 ± 1.76
OSI AU
584.88
472.62*
SOD NU/ml
14.73 (9.63–20.25)
13.61 (7.4–20.1)
MnSOD NU/ml
7.70 (2.58–16.42)
7.55 (2.51–15.65)
CuZnSOD NU/mg
7.03 (2.9–10.88)
6.06 (0.74–11.83)*
SH umol/g protein
2.72 (0.97–3.79)
2.72 (1.01–4.00)
CER mg/dl
20.49 (5.56–43.22)
24.04 (9.47–58.37)*
LHP mmol/l
3.35 ± 1.83
2.05 ± 1.98*
MDA mol/g of protein
6.24 ± 1.58
5.96 ± 1.54
Mann–Whitney U-test was applied. The data were presented as median (minimum–maximum) unless stated otherwise
pre-PTX before parathyroidectomy, post-PTX 15 days after parathyroidectomy, TAC total antioxidant capacity, TOS total oxidant status, OSI oxidative stress index, SOD superoxide dismutase, MnSOD mitochondrial form SOD, CuZnSOD cytoplasmic form SOD, SH sulfhydryl groups, CER ceruloplasmin, LHP lipid hydroperoxides, MDA malondialdehyde
*Significant P-value (P < 0.05)

The correlation of angiogenesis in the parathyroid tissue with the parameters of oxidative stress

The expression of angiogenic factors: VEGF, CD31, CD106 in parathyroid tissue was negatively correlated with the changes of the TOS, TAC, SOD, and LHP but positively correlated with MDA. There was no statistical significance in the study group patients (Table 3). The correlation level was low and medium. Among the studied biochemical parameters, the correlation between the expression of angiogenic factors with serum parathyroid hormone is noteworthy (Table 4).
Table 3
The correlation between stress markers and angiogenic factors in parathyroid tissue in patients with PHPT. No significant relationship between the angiogenesis and systemic changes in oxidative stress in patients operated due to primary hyperparathyroidism was demonstrated
Stress markers
correlation factor r
TOS
TAC
SOD
LHP
MDA
VEGF+
pre-PTX
0.22
0.44
0.05
−0.12
0.13
post-PTX
−0.23
−0.17
−0.05
−0.28
0.24
CD31+
pre-PTX
0.29
0.44
0.12
−0.02
0.15
post-PTX
−0.42
−0.05
−0.08
−0.37
0.22
CD106+
pre-PTX
0.11
0.33
0.13
−0.03
0.03
post-PTX
−0.39
0.06
0.17
−0.36
0.02
Mann–Whitney U-test was applied
pre-PTX before parathyroidectomy, post-PTX 15 days after parathyroidectomy, TAC total antioxidant capacity, TOS total oxidant status, SOD superoxide dismutase, LHP lipid hydroperoxides, MDA malondialdehyde, VEGF vascular endothelial growth factor, CD31 platelet endothelial cell adhesion molecule, CD106 vascular cell adhesion molecule-1
Table 4
The correlation between the changes of serum PTH level and angiogenic parameters in parathyroid tissue. A strong correlation between PTH level and the expression of all angiogenesis markers, including VEGF, CD31, and CD106, was revealed, which proves that parathormone is implicated in angiogenesis in the parathyroid glands
 
PTH pre-PTX
544.21 µmol/l ± 793.77
PTH post-PTX
27.90 µmol/l ± 32.34
VEGF+
r = 0.65*
r = 0.67*
CD31+
r = 0.52*
r = 0.36
CD106+
r = 0.50*
r = 0.56*
Mann–Whitney U-test was applied
pre-PTX before parathyroidectomy, post-PTX 15 days after parathyroidectomy, VEGF vascular endothelial growth factor, CD31 platelet endothelial cell adhesion molecule, CD106 vascular cell adhesion molecule-1
*Significant P-value (P < 0.05)

Discussion

Our study demonstrated decreased oxidative stress markers after parathyroidectomy, which may be one of the reasons of decreased probability of cardiovascular events and a survival benefit. In the postoperative period in patients with primary hyperparathyroidism, a significant increase of the total antioxidant capacity and a reduction of total oxidative status were revealed. Moreover, a considerable decrease in the oxidative stress index was demonstrated, which was the result of down-regulation of oxidative stress in postoperative period. Among measured antioxidants, we observed a significant decrease in serum level of SOD, mainly in cytoplasmic form CuZnSOD, which was due to decrease in production of superoxide anion, associated with the normalization of parathormone levels, and the significant increase of ceruloplasmin. Malondialdehyde concentration in the blood of patients with primary hyperparathyroidism was reduced, which was probably triggered by the inhibition of lipid peroxidation. These data confirmed the previous study by Tanaka et al., which showed the case of primary hyperparathyroidism, in which oxidative stress was significantly lower after parathyroidectomy [44]. The results suggest that parathyroidectomy reduces oxidative stress in patients with primary hyperparathyroidism, which may in part explain reduced risk of cardiovascular and all-cause mortality after parathyroidectomy.
Nevertheless, the reason for decreased oxidative stress after parathyroidectomy is still not completely known. We could suspect that the surgery could cause the changes in oxidative status; however, the surgery itself is a widely known factor triggering ROS production [45, 46]. What is more, surgical trauma is responsible for metastasis development and promotion of tumor growth postoperatively, and this complication is related to ROS-rich environment in the postoperative period [47, 48]. On the other hand, Kaçmaz et al. revealed that nitric oxide and malondialdehyde levels were enhanced and catalase levels were decreased in patients after both thyroidectomy and thyroparathyroidectomy [49].
Another factor involved in changes in oxidative stress could be the level of calcium (Ca). The excessive accumulation of Ca in mitochondria induces membrane permeability transition, release of cytochrome c, respiratory inhibition, and ROS production. The mitochondrial Ca overload also results in oxidative stress in cardiomyocytes after ischemia-reperfusion. Ca overload and oxidative and nitrosative stress in peripheral blood mononuclear cell (PBMC) lead to higher production of hydrogen dioxide (H2O2) and in turn take part in transmitting signals activating PBMC. Previous parathyroidectomy inhibits ROS synthesis [13].
Several studies suggested that parathormone could be the factor implicated in oxidative stress imbalance and causally involved in pathological processes leading to cardiovascular disease. After parathyroidectomy, serum PTH decreases rapidly to reach physiological values. Higher plasma PTH was associated with higher risk for cardiovascular mortality independently of established cardiovascular risk factors and factors associated with mineral homeostasis [50, 51]. Sambrook et al. found that serum PTH was correlated with increased mortality in the frail elderly, regardless renal parameters, vitamin D levels, and bone mass assessed by ultrasound examinations [52]. Higher PTH levels were associated with increased mortality and severity of illness in critically ill patients in an emergency or intensive care department, independently of serum calcium levels. Increased PTH concentration was also correlated with enhanced fatty acid oxidation in the myocardium in animals with secondary hyperparathyroidism caused by chronic renal failure [53]. In accordance with this research are the results of experimental studies which revealed PTH receptors in vascular endothelial cells, suggesting that the endothelium is a target organ of PTH [54, 55].
There are several possible explanations for the impact of PTH on cardiovascular mortality. PTH is responsible for regulating the level of ionized calcium via stimulation of osteoclastic bone resorption, stimulation of calcium reabsorption in the distal tubule of the kidney, and activation of 25-hydroxyvitamin D 1‑alpha hydroxylase in the proximal renal tubule. The imbalance in mineral homeostasis leads to cardiovascular complications. PTH is also involved in vascular calcification and remodeling and therefore causes atherogenesis [5658]. Excessive levels of PTH result in ventricular hypertrophy, cardiac calcification, and fibrosis [5961]. Moreover, up-regulated PTH concentrations have been implicated in inflammation, raised systolic blood pressure, and increased body mass index [4, 6264]. Therefore, the impact of parathormone on oxidative stress in patients with primary hyperparathyroidism may also be one of the factors implicated in the pathogenesis of cardiovascular complications in primary HPT.
Oxidative stress also plays a huge role in the process of angiogenesis. This process is necessary when a tumor reaches a critical volume, which is approximately 1–2 mm3, in order to continue its expansion [65, 66]. Nicotinamide adenine dinucleotide phosphate oxidases (Nox)-derived ROS and VEGF promote the angiogenic switch in cancer cells [67, 68]. Nox-derived ROS play a role not only in pathological states, but also via H2O2 synthesis contribute to the processes of angiogenesis and tissue repair [6972]. Reactive oxygen species stimulate the activation of hypoxia-inducible factor 1‑alpha (HIF-1α) and thus enhance VEGF expression. When VEGF binds to VEGF receptor 2, it triggers ROS release, which is implicated in basement membrane degradation, migration, proliferation, and vessel formation [68, 73, 74].
In our study no significant relationship between the angiogenesis and systemic changes in oxidative stress in patients who underwent surgery due to primary hyperparathyroidism was demonstrated. There was no significant correlation between the changes in both the level of antioxidants, as well as lipid peroxidation products and the expression of angiogenic markers. Nevertheless, endothelial cells are highly heterogeneous and it is suggested that the panendothelial cell markers are not ideal indicators of pathological or activated neovessels. However, there was a strong correlation between PTH level and the expression of all angiogenesis markers, including VEGF, CD31, and CD106, which proves that parathormone is implicated in angiogenesis in the parathyroid glands.
In conclusion, this study showed that parathyroidectomy was a procedure of a great importance to reduce oxidation processes in patients with PHPT. The reduction of the level of parathormone in the postoperative period plays a crucial role in the down-regulation of free radical production and lowers the mortality of patients with PHPT from cardiovascular diseases. It has not been established what time is required to obtain a complete normalization of blood parameters. The mechanism of oxidative stress in the parathyroid gland is a complex process depending on many factors, among which of great importance is PTH. The phenomenon of angiogenesis in the parathyroid glands is also associated with parathormone, due to the strong correlation between these parameters. Even if a great number of studies have been performed recently, the mechanisms implicated in the pathogenesis of primary hyperparathyroidism and processes occurring after surgical resection are still not completely known. A better understanding of these issues could result in more precise assessment of diagnosis and more effective treatment, especially in those cases, in which commonly used parameters are insufficient. Studies of this type should be continued and new insight may in the future result in targeted therapy or possibly prevention.
Open access funding provided by Medical University of Silesia.

Conflict of interest

M. Deska, E. Romuk, O.A. Segiet, G. Buła, W. Truchanowski, D. Stolecka, E. Birkner and J. Gawrychowski declare that they have no competing interests.
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Literatur
2.
Zurück zum Zitat Adami S, Marocci C, Gatti D. Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res. 2002;17(Suppl 2):18–23. Adami S, Marocci C, Gatti D. Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res. 2002;17(Suppl 2):18–23.
3.
Zurück zum Zitat Walgenbach S, Hommel G, Junginger T. Outcome after surgery for primary hyperparathyroidism: ten-year prospective follow-up study. World J Surg. 2000;24(5):564–9. CrossRefPubMed Walgenbach S, Hommel G, Junginger T. Outcome after surgery for primary hyperparathyroidism: ten-year prospective follow-up study. World J Surg. 2000;24(5):564–9. CrossRefPubMed
4.
Zurück zum Zitat Andersson P, Rydberg E, Willenheimer R. Primary hyperparathyroidism and heart disease – a review. Eur Heart J. 2004;25:1776–87. CrossRefPubMed Andersson P, Rydberg E, Willenheimer R. Primary hyperparathyroidism and heart disease – a review. Eur Heart J. 2004;25:1776–87. CrossRefPubMed
5.
Zurück zum Zitat Ybarra J, Doñate T, Jurado J, et al. Primary hyperparathyroidism, insulin resistance, and cardiovascular disease: a review. Nurs Clin North Am. 2007;42:79–85. CrossRefPubMed Ybarra J, Doñate T, Jurado J, et al. Primary hyperparathyroidism, insulin resistance, and cardiovascular disease: a review. Nurs Clin North Am. 2007;42:79–85. CrossRefPubMed
6.
Zurück zum Zitat Lind L, Skarfors E, Berglund L, et al. Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol. 1997;50:967–73. CrossRefPubMed Lind L, Skarfors E, Berglund L, et al. Serum calcium: a new, independent, prospective risk factor for myocardial infarction in middle-aged men followed for 18 years. J Clin Epidemiol. 1997;50:967–73. CrossRefPubMed
7.
Zurück zum Zitat Giovannucci E, Liu Y, Hollis BW, et al. 25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174–80. CrossRefPubMedPubMedCentral Giovannucci E, Liu Y, Hollis BW, et al. 25-Hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174–80. CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat Tanko LB, Christiansen C, Cox DA, et al. Relationship between osteoporosis and cardiovascular disease in postmenopausal women. J Bone Miner Res. 2005;20:1912–20. CrossRefPubMed Tanko LB, Christiansen C, Cox DA, et al. Relationship between osteoporosis and cardiovascular disease in postmenopausal women. J Bone Miner Res. 2005;20:1912–20. CrossRefPubMed
9.
Zurück zum Zitat Dhingra R, Sullivan LM, Fox CS, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med. 2007;167:879–85. CrossRefPubMed Dhingra R, Sullivan LM, Fox CS, et al. Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community. Arch Intern Med. 2007;167:879–85. CrossRefPubMed
10.
Zurück zum Zitat Taki K, Takayama F, Tsuruta Y, et al. Oxidative stress, advanced glycation end product, and coronary artery calcification in hemodialysis patients. Kidney Int. 2006;70:218–24. CrossRefPubMed Taki K, Takayama F, Tsuruta Y, et al. Oxidative stress, advanced glycation end product, and coronary artery calcification in hemodialysis patients. Kidney Int. 2006;70:218–24. CrossRefPubMed
11.
Zurück zum Zitat Descamps-Latscha B, Witko-Sarsat V. Importance of oxidatively modified proteins in chronic renal failure. Kidney Int Suppl. 2001;78:S108–S113. CrossRefPubMed Descamps-Latscha B, Witko-Sarsat V. Importance of oxidatively modified proteins in chronic renal failure. Kidney Int Suppl. 2001;78:S108–S113. CrossRefPubMed
12.
Zurück zum Zitat Brunner H, Cockcroft JR, Deanfield J, et al. Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23:233–46. CrossRefPubMed Brunner H, Cockcroft JR, Deanfield J, et al. Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23:233–46. CrossRefPubMed
13.
Zurück zum Zitat Vidal A, Sun Y, Bhattacharya SK, et al. Calcium paradox of aldosteronism and the role of the parathyroid glands. Am J Physiol Heart Circ Physiol. 2006;290:H286–H294. CrossRefPubMed Vidal A, Sun Y, Bhattacharya SK, et al. Calcium paradox of aldosteronism and the role of the parathyroid glands. Am J Physiol Heart Circ Physiol. 2006;290:H286–H294. CrossRefPubMed
14.
Zurück zum Zitat Niki E. Assessment of antioxidant capacity in vitro and in vivo. Free Radic Bio Med. 2010;49(4):503–15. CrossRef Niki E. Assessment of antioxidant capacity in vitro and in vivo. Free Radic Bio Med. 2010;49(4):503–15. CrossRef
15.
Zurück zum Zitat Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4‑hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438. CrossRefPubMedPubMedCentral Ayala A, Muñoz MF, Argüelles S. Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4‑hydroxy-2-nonenal. Oxid Med Cell Longev. 2014;2014:360438. CrossRefPubMedPubMedCentral
16.
17.
Zurück zum Zitat McCay PB, Gibson DD, Hornbrook KR. Glutathione-dependent inhibition of lipid peroxidation by a soluble, heatlabile factor, not glutathione peroxidase. Fed Proc. 1981;40:199–205. PubMed McCay PB, Gibson DD, Hornbrook KR. Glutathione-dependent inhibition of lipid peroxidation by a soluble, heatlabile factor, not glutathione peroxidase. Fed Proc. 1981;40:199–205. PubMed
18.
Zurück zum Zitat Dalle-Donne I, Rossi R, Colombo R, et al. Biomarkers of oxidative damage in human disease. Clin Chem. 2006;52(4):601–23. CrossRefPubMed Dalle-Donne I, Rossi R, Colombo R, et al. Biomarkers of oxidative damage in human disease. Clin Chem. 2006;52(4):601–23. CrossRefPubMed
19.
Zurück zum Zitat Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002;33(3):337–49. CrossRefPubMed Zelko IN, Mariani TJ, Folz RJ. Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radic Biol Med. 2002;33(3):337–49. CrossRefPubMed
21.
Zurück zum Zitat Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta. 2013;1830(5):3289–303. CrossRefPubMed Brigelius-Flohé R, Maiorino M. Glutathione peroxidases. Biochim Biophys Acta. 2013;1830(5):3289–303. CrossRefPubMed
22.
Zurück zum Zitat Craige SM, Kant S, Keaney JF Jr.. Reactive oxygen species in endothelial function – from disease to adaptation. Circ J. 2015;79(6):1145–55. CrossRefPubMed Craige SM, Kant S, Keaney JF Jr.. Reactive oxygen species in endothelial function – from disease to adaptation. Circ J. 2015;79(6):1145–55. CrossRefPubMed
23.
Zurück zum Zitat Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia. Angiogenesis. 2008;11(2):121–40. CrossRefPubMed Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia. Angiogenesis. 2008;11(2):121–40. CrossRefPubMed
24.
25.
Zurück zum Zitat Carter WB, Crowell SL, Boswell CA, et al. Stimulation of angiogenesis by canine parathyroid tissue. Surgery. 1996;120:1089–94. CrossRefPubMed Carter WB, Crowell SL, Boswell CA, et al. Stimulation of angiogenesis by canine parathyroid tissue. Surgery. 1996;120:1089–94. CrossRefPubMed
26.
Zurück zum Zitat Carter WB, Uy K, Ward MD, et al. Parathyroid-induced angiogenesis is VEGF-dependent. Surgery. 2000;128:458–64. CrossRefPubMed Carter WB, Uy K, Ward MD, et al. Parathyroid-induced angiogenesis is VEGF-dependent. Surgery. 2000;128:458–64. CrossRefPubMed
27.
Zurück zum Zitat Kikumori T, Imai T, Tanaka Y, et al. Parathyroid autotransplantation with total thyroidectomy for thyroid carcinoma: long-term follow-up of grafted parathyroid function. Surgery. 1999;125:504–8. CrossRefPubMed Kikumori T, Imai T, Tanaka Y, et al. Parathyroid autotransplantation with total thyroidectomy for thyroid carcinoma: long-term follow-up of grafted parathyroid function. Surgery. 1999;125:504–8. CrossRefPubMed
28.
Zurück zum Zitat Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. CrossRefPubMed Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76. CrossRefPubMed
29.
Zurück zum Zitat Kranz A, Mattfeldt T, Waltenberger J. Molecular mediators of tumor angiogenesis: enhanced expression and activation of vascular endothelial growth factor receptor KDR in primary breast cancer. Int J Cancer. 1999;84:293–8. CrossRefPubMed Kranz A, Mattfeldt T, Waltenberger J. Molecular mediators of tumor angiogenesis: enhanced expression and activation of vascular endothelial growth factor receptor KDR in primary breast cancer. Int J Cancer. 1999;84:293–8. CrossRefPubMed
30.
Zurück zum Zitat Wechsel HW, Bichler KH, Feil G, et al. Renal cell carcinoma: relevance of angiogenetic factors. Anticancer Res. 1999;19(2C):1537–40. PubMed Wechsel HW, Bichler KH, Feil G, et al. Renal cell carcinoma: relevance of angiogenetic factors. Anticancer Res. 1999;19(2C):1537–40. PubMed
31.
Zurück zum Zitat Wong MP, Cheung N, Yuen ST, et al. Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumour progression. Int J Cancer. 1999;81:845–50. CrossRefPubMed Wong MP, Cheung N, Yuen ST, et al. Vascular endothelial growth factor is up-regulated in the early pre-malignant stage of colorectal tumour progression. Int J Cancer. 1999;81:845–50. CrossRefPubMed
32.
Zurück zum Zitat Isowa S, Shimo T, Ibaragi S, et al. PTHrP regulates angiogenesis and bone resorption via VEGF expression. Anticancer Res. 2010;30(7):2755–67. PubMed Isowa S, Shimo T, Ibaragi S, et al. PTHrP regulates angiogenesis and bone resorption via VEGF expression. Anticancer Res. 2010;30(7):2755–67. PubMed
33.
Zurück zum Zitat Uchida M, Yamato H, Nagai Y, et al. Parathyroid hormone increases the expression level of matrix metalloproteinase-13 in vivo. J Bone Miner Metab. 2001;19(4):207–12. CrossRefPubMed Uchida M, Yamato H, Nagai Y, et al. Parathyroid hormone increases the expression level of matrix metalloproteinase-13 in vivo. J Bone Miner Metab. 2001;19(4):207–12. CrossRefPubMed
34.
Zurück zum Zitat Albelda SM, Muller WA, Buck CA, et al. Molecular and cellular properties of PECAM-1 (endoCAM/CD31): a novel vascular cell-cell adhesion molecule. J Cell Biol. 1991;114:1059–68. CrossRefPubMed Albelda SM, Muller WA, Buck CA, et al. Molecular and cellular properties of PECAM-1 (endoCAM/CD31): a novel vascular cell-cell adhesion molecule. J Cell Biol. 1991;114:1059–68. CrossRefPubMed
35.
Zurück zum Zitat Cao G, O’Brien CD, Zhou Z, et al. Involvement of human PECAM-1 in angiogenesis and in vitro endothelial cell migration. Am J Physiol Cell Physiol. 2002;282(5):C1181–90. CrossRefPubMed Cao G, O’Brien CD, Zhou Z, et al. Involvement of human PECAM-1 in angiogenesis and in vitro endothelial cell migration. Am J Physiol Cell Physiol. 2002;282(5):C1181–90. CrossRefPubMed
36.
Zurück zum Zitat Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767–804. CrossRefPubMed Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol. 1993;11:767–804. CrossRefPubMed
37.
Zurück zum Zitat Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38:1103–11. CrossRefPubMed Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005;38:1103–11. CrossRefPubMed
38.
Zurück zum Zitat Erel O. A novel automated direct measurement method for measuring total antioxidant capacity. Clin Biochem. 2004;37:277–85. CrossRefPubMed Erel O. A novel automated direct measurement method for measuring total antioxidant capacity. Clin Biochem. 2004;37:277–85. CrossRefPubMed
39.
Zurück zum Zitat Oyanagui Y. Reevaluation of assay methods and establishment of kit for superoxide dismutase activity. Anal Biochem. 1984;142:290–6. CrossRefPubMed Oyanagui Y. Reevaluation of assay methods and establishment of kit for superoxide dismutase activity. Anal Biochem. 1984;142:290–6. CrossRefPubMed
40.
41.
Zurück zum Zitat Richterich R. Clin chem. PZWL, Warsaw 1971; 205–207. Richterich R. Clin chem. PZWL, Warsaw 1971; 205–207.
42.
Zurück zum Zitat Södergren E, Nourooz-Zadeh J, Berglund L, et al. Re-evaluation of the ferrous oxidation in xylenol orange assay for the measurement of plasma lipid hydroperoxides. J Biochem Biophys Methods. 1998;37:137–46. CrossRefPubMed Södergren E, Nourooz-Zadeh J, Berglund L, et al. Re-evaluation of the ferrous oxidation in xylenol orange assay for the measurement of plasma lipid hydroperoxides. J Biochem Biophys Methods. 1998;37:137–46. CrossRefPubMed
43.
Zurück zum Zitat Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8. CrossRefPubMed Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95:351–8. CrossRefPubMed
44.
Zurück zum Zitat Tanaka M, Tokunaga K, Maruyama T, et al. Parathyroidectomy markedly reduces oxidative stress in a patient with primary hyperparathyroidism. Ther Apher Dial. 2011;15(Suppl 1):38–41. CrossRefPubMed Tanaka M, Tokunaga K, Maruyama T, et al. Parathyroidectomy markedly reduces oxidative stress in a patient with primary hyperparathyroidism. Ther Apher Dial. 2011;15(Suppl 1):38–41. CrossRefPubMed
45.
Zurück zum Zitat Fricova J, Stopka P, Krizova J, et al. The effect of laparotomy on hydroxyl radicals, singlet oxygen and antioxidants measured by EPR method in the tails of rats. Neuro Endocrinol Lett. 2009;30(e6):373. PubMed Fricova J, Stopka P, Krizova J, et al. The effect of laparotomy on hydroxyl radicals, singlet oxygen and antioxidants measured by EPR method in the tails of rats. Neuro Endocrinol Lett. 2009;30(e6):373. PubMed
46.
Zurück zum Zitat ten Kate M, van der Wal JBC, Sluiter W, et al. The role of superoxide anions in the development of distant tumour recurrence. Br J Cancer. 2006;95:1497–503. CrossRefPubMedPubMedCentral ten Kate M, van der Wal JBC, Sluiter W, et al. The role of superoxide anions in the development of distant tumour recurrence. Br J Cancer. 2006;95:1497–503. CrossRefPubMedPubMedCentral
47.
Zurück zum Zitat Coffey JC, Wang JH, Smith MJ, et al. Excisional surgery for cancer cure: therapy at a cost. Lancet Oncol. 2003;4:760e8. CrossRef Coffey JC, Wang JH, Smith MJ, et al. Excisional surgery for cancer cure: therapy at a cost. Lancet Oncol. 2003;4:760e8. CrossRef
48.
Zurück zum Zitat O’Leary DP, Wang JH, Cotter TG, et al. Less stress, more success? Oncological implications of surgery-induced oxidative stress. Gut. 2013;62(3):461–70. CrossRefPubMed O’Leary DP, Wang JH, Cotter TG, et al. Less stress, more success? Oncological implications of surgery-induced oxidative stress. Gut. 2013;62(3):461–70. CrossRefPubMed
49.
Zurück zum Zitat Kaçmaz M, Atmaca M, Arslan A, et al. Oxidative stress in patients with thyroidectomy and thyroparathyroidectomy under replacement therapy. Endocrine. 2015;48(1):227–32. CrossRefPubMed Kaçmaz M, Atmaca M, Arslan A, et al. Oxidative stress in patients with thyroidectomy and thyroparathyroidectomy under replacement therapy. Endocrine. 2015;48(1):227–32. CrossRefPubMed
50.
Zurück zum Zitat Hagström E, Hellman P, Larsson TE. Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation. 2009;119(21):2765–71. CrossRefPubMed Hagström E, Hellman P, Larsson TE. Plasma parathyroid hormone and the risk of cardiovascular mortality in the community. Circulation. 2009;119(21):2765–71. CrossRefPubMed
51.
Zurück zum Zitat Vestergaard H, Ostergaard Kristensen L. Normocalcemia and persistent elevated serum concentrations of 1–84 parathyroid hormone after operation for sporadic parathyroid adenoma: evidence of increased morbidity from cardiovascular disease. World J Surg. 2002;26:657–60. CrossRefPubMed Vestergaard H, Ostergaard Kristensen L. Normocalcemia and persistent elevated serum concentrations of 1–84 parathyroid hormone after operation for sporadic parathyroid adenoma: evidence of increased morbidity from cardiovascular disease. World J Surg. 2002;26:657–60. CrossRefPubMed
52.
Zurück zum Zitat Sambrook PN, Chen JS, March LM, et al. Serum parathyroid hormone is associated with increased mortality independent of 25-hydroxy vitamin D status, bone mass, and renal function in the frail and very old: a cohort study. J Clin Endocrinol Metab. 2004;89:5477–81. CrossRefPubMed Sambrook PN, Chen JS, March LM, et al. Serum parathyroid hormone is associated with increased mortality independent of 25-hydroxy vitamin D status, bone mass, and renal function in the frail and very old: a cohort study. J Clin Endocrinol Metab. 2004;89:5477–81. CrossRefPubMed
53.
Zurück zum Zitat Smogorzewski M, Perna AF, Borum PR, et al. Fatty acid oxidation in the myocardium: effects of parathyroid hormone and CRF. Kidney Int. 1988;34:797–803. CrossRefPubMed Smogorzewski M, Perna AF, Borum PR, et al. Fatty acid oxidation in the myocardium: effects of parathyroid hormone and CRF. Kidney Int. 1988;34:797–803. CrossRefPubMed
54.
Zurück zum Zitat Jiang B, Morimoto S, Yang J, et al. Expression of parathyroid hormone/parathyroid hormone-related protein receptor in vascular endothelial cells. J Cardiovasc Pharmacol. 1998;31(Suppl 1):S142–S144. CrossRefPubMed Jiang B, Morimoto S, Yang J, et al. Expression of parathyroid hormone/parathyroid hormone-related protein receptor in vascular endothelial cells. J Cardiovasc Pharmacol. 1998;31(Suppl 1):S142–S144. CrossRefPubMed
55.
Zurück zum Zitat Isales CM, Sumpio B, Bollag RJ, et al. Functional parathyroid hormone receptors are present in an umbilical vein endothelial cell line. Am J Physiol Endocrinol Metab. 2000;279:E654–E662. PubMed Isales CM, Sumpio B, Bollag RJ, et al. Functional parathyroid hormone receptors are present in an umbilical vein endothelial cell line. Am J Physiol Endocrinol Metab. 2000;279:E654–E662. PubMed
56.
Zurück zum Zitat Perkovic V, Hewitson TD, Kelynack KJ, et al. Parathyroid hormone has a prosclerotic effect on vascular smooth muscle cells. Kidney Blood Press Res. 2003;26:27–33. CrossRefPubMed Perkovic V, Hewitson TD, Kelynack KJ, et al. Parathyroid hormone has a prosclerotic effect on vascular smooth muscle cells. Kidney Blood Press Res. 2003;26:27–33. CrossRefPubMed
57.
Zurück zum Zitat Rashid G, Bernheim J, Green J, et al. Parathyroid hormone stimulates endothelial expression of atherosclerotic parameters through protein kinase pathways. Am J Physiol Renal Physiol. 2007;292:F1215–F1218. CrossRefPubMed Rashid G, Bernheim J, Green J, et al. Parathyroid hormone stimulates endothelial expression of atherosclerotic parameters through protein kinase pathways. Am J Physiol Renal Physiol. 2007;292:F1215–F1218. CrossRefPubMed
58.
Zurück zum Zitat Amann K, Tornig J, Flechtenmacher C, et al. Blood-pressure-independent wall thickening of intramyocardial arterioles in experimental uraemia: evidence for a permissive action of PTH. Nephrol Dial Transplant. 1995;10:2043–8. PubMed Amann K, Tornig J, Flechtenmacher C, et al. Blood-pressure-independent wall thickening of intramyocardial arterioles in experimental uraemia: evidence for a permissive action of PTH. Nephrol Dial Transplant. 1995;10:2043–8. PubMed
59.
Zurück zum Zitat Saleh FN, Schirmer H, Sundsfjord J, et al. Parathyroid hormone and left ventricular hypertrophy. Eur Heart J. 2003;24:2054–60. CrossRefPubMed Saleh FN, Schirmer H, Sundsfjord J, et al. Parathyroid hormone and left ventricular hypertrophy. Eur Heart J. 2003;24:2054–60. CrossRefPubMed
60.
Zurück zum Zitat Di Leo C, Gallieni M, Bestetti A, et al. Cardiac and pulmonary calcification in a hemodialysis patient: partial regression 4 years after parathyroidectomy. Clin Nephrol. 2003;59(1):59–63. CrossRefPubMed Di Leo C, Gallieni M, Bestetti A, et al. Cardiac and pulmonary calcification in a hemodialysis patient: partial regression 4 years after parathyroidectomy. Clin Nephrol. 2003;59(1):59–63. CrossRefPubMed
61.
Zurück zum Zitat Amann K, Ritz E, Wiest G, et al. A role of parathyroid hormone for the activation of cardiac fibroblasts in uremia. J Am Soc Nephrol. 1994;4(10):1814–9. PubMed Amann K, Ritz E, Wiest G, et al. A role of parathyroid hormone for the activation of cardiac fibroblasts in uremia. J Am Soc Nephrol. 1994;4(10):1814–9. PubMed
62.
Zurück zum Zitat Jorde R, Svartberg J, Sundsfjord J. Serum parathyroid hormone as a predictor of increase in systolic blood pressure in men. J Hypertens. 2005;23:1639–44. CrossRefPubMed Jorde R, Svartberg J, Sundsfjord J. Serum parathyroid hormone as a predictor of increase in systolic blood pressure in men. J Hypertens. 2005;23:1639–44. CrossRefPubMed
63.
Zurück zum Zitat Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone level is associated with body mass index: the 5th Tromsø study. Eur J Endocrinol. 2004;151:167–72. CrossRefPubMed Kamycheva E, Sundsfjord J, Jorde R. Serum parathyroid hormone level is associated with body mass index: the 5th Tromsø study. Eur J Endocrinol. 2004;151:167–72. CrossRefPubMed
64.
Zurück zum Zitat Øgard CG, Engelmann MD, Kistorp C, et al. Increased plasma N‑terminal pro-B-type natriuretic peptide and markers of inflammation related to atherosclerosis in patients with primary hyperparathyroidism. Clin Endocrinol. 2005;63:493–8. CrossRef Øgard CG, Engelmann MD, Kistorp C, et al. Increased plasma N‑terminal pro-B-type natriuretic peptide and markers of inflammation related to atherosclerosis in patients with primary hyperparathyroidism. Clin Endocrinol. 2005;63:493–8. CrossRef
65.
Zurück zum Zitat Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6. CrossRefPubMed Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6. CrossRefPubMed
67.
Zurück zum Zitat Katsabeki-Katsafli A, Kerenidi T, Kostikas K, et al. Serum vascular endothelial growth factor is related to systemic oxidative stress in patients with lung cancer. Lung Cancer. 2008;60:271e6. CrossRef Katsabeki-Katsafli A, Kerenidi T, Kostikas K, et al. Serum vascular endothelial growth factor is related to systemic oxidative stress in patients with lung cancer. Lung Cancer. 2008;60:271e6. CrossRef
68.
Zurück zum Zitat Arbiser JL, Petros J, Klafter R, et al. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci USA. 2002;99:715–20. CrossRefPubMedPubMedCentral Arbiser JL, Petros J, Klafter R, et al. Reactive oxygen generated by Nox1 triggers the angiogenic switch. Proc Natl Acad Sci USA. 2002;99:715–20. CrossRefPubMedPubMedCentral
69.
Zurück zum Zitat Craige SM, Chen K, Pei Y, et al. NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation. Circulation. 2011;124:731–40. CrossRefPubMedPubMedCentral Craige SM, Chen K, Pei Y, et al. NADPH oxidase 4 promotes endothelial angiogenesis through endothelial nitric oxide synthase activation. Circulation. 2011;124:731–40. CrossRefPubMedPubMedCentral
70.
Zurück zum Zitat Burgoyne JR, Madhani M, Cuello F, et al. Cysteine redox sensor in PKGIa enables oxidantinduced activation. Science. 2007;317:1393–7. CrossRefPubMed Burgoyne JR, Madhani M, Cuello F, et al. Cysteine redox sensor in PKGIa enables oxidantinduced activation. Science. 2007;317:1393–7. CrossRefPubMed
71.
72.
Zurück zum Zitat Oshikawa J, Urao N, Kim HW, et al. Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLOS ONE. 2010;5:e10189. CrossRefPubMedPubMedCentral Oshikawa J, Urao N, Kim HW, et al. Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLOS ONE. 2010;5:e10189. CrossRefPubMedPubMedCentral
73.
Zurück zum Zitat Xia C, Meng Q, Liu LZ, et al. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 2007;67:10823–30. CrossRefPubMed Xia C, Meng Q, Liu LZ, et al. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res. 2007;67:10823–30. CrossRefPubMed
74.
Zurück zum Zitat Zhang M, Brewer AC, Schröder K, et al. NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci USA. 2010;107(42):18121–6. CrossRefPubMedPubMedCentral Zhang M, Brewer AC, Schröder K, et al. NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis. Proc Natl Acad Sci USA. 2010;107(42):18121–6. CrossRefPubMedPubMedCentral
Metadaten
Titel
Oxidative stress and angiogenesis in primary hyperparathyroidism
verfasst von
Mariusz Deska
Ewa Romuk
Oliwia Anna Segiet
Grzegorz Buła
Witold Truchanowski
Dominika Stolecka
Ewa Birkner
Jacek Gawrychowski
Publikationsdatum
01.06.2017
Verlag
Springer Vienna
Erschienen in
European Surgery / Ausgabe 3/2017
Print ISSN: 1682-8631
Elektronische ISSN: 1682-4016
DOI
https://doi.org/10.1007/s10353-016-0457-6

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