Increased levels of thioredoxin in patients with abdominal aortic aneurysms (AAAs). A potential link of oxidative stress with AAA evolution
Introduction
Abdominal aortic aneurysm (AAA) is an important health problem in elderly. In cross-sectional studies the prevalence varies from 3% to 8%. In elderly men AAA may cause as much as 2–3% of all deaths. The incidence of asymptomatic and ruptured AAA has increased during the last decades [1].
Efforts to limit the mortality rate from AAA rupture depend on early detection and elective AAA repair. The indication for elective repair preventing rupture is mainly based upon the maximal diameter of AAA above 5 or 5.5 cm. The benefit of early detection of AAAs by ultrasound screening is limited because most AAAs are too small to operate at the time of diagnosis, early repair of small AAA has been demonstrated to be inefficient and there is currently no established treatment for small AAAs [2], [3]. Most AAAs shows discontinuous growth patterns and alternate periods of stability and non-growth with periods of acute expansion and occasionally rupture. In this respect, the diameter of the AAA is a surrogate marker of the growth rate, which reflects the magnitude of the degenerative process of the wall, and thus becomes a surrogate marker of rupture. Consequently, biomarkers of size, growth and rupture could give us a more nuanced indication for surgery. Moreover, identification of such biomarkers could also afford novel pathogenic pathways and may thus open possibilities for pharmacological inhibition of growth, providing tools for monitoring this inhibition [4].
AAA are characterized by the presence of a mural hemo-thrombus containing non-cellular and cellular blood components including platelets, red blood cells (RBCs) and polymorphonuclear neutrophils (PMN) which represent the major class of leukocytes, particularly abundant within the luminal layer of the thrombus. Upon activation, PMN release proteases but also myeloperoxidase (MPO) causing oxidative damages. The combination of NADPH oxidase, NO synthase and MPO leads to the production of a variety of reactive oxygen species such as superoxide anion, hydroxyl radicals or peroxynitrite. In addition, the trapping of RBCs within the thrombus may lead to hemolysis and subsequent release of the pro-oxidant hemoglobin, in particular able to generate OH° from H2O2 by the Fenton reaction. This biological activity of the luminal layer of the thrombus is therefore a source of potential biomarkers coming from activated or dying PMNs and RBCs. Thioredoxin (TRX) is an important intracellular antioxidant enzyme that is elevated in plasma of patients with coronary atherosclerosis [5], [6] and associated with the presence of intraplaque hemorrhage [7]. In the present work, we sought for the presence of TRX in the AAA thrombus, which could be released into the blood compartment. We thus assessed TRX in conditioned media from the different layers of AAA thrombus, and then in the serum of patients with AAA.
Section snippets
AAA tissue and tissue-conditioned media
Ten AAA thrombus samples were collected during surgical repair and dissected into luminal and abluminal parts (respectively at the interface with circulating blood and with the remaining media). AAA samples were obtained from patients undergoing surgery, enrolled in the RESAA protocol (REflet Sanguin de l’évolutivité des Anévrysmes de l’Aorte abdominale, CCPPRB Paris-Cochin n° 2095, n° 1930 and n° 1931) [8]. All patients gave their informed written consent, and the protocol was approved by a
TRX is mainly localized and released by the luminal part of AAA thrombus
We first analysed the presence and localization of TRX in human AAA thrombus. As shown in Fig. 1A, the luminal part of the thrombus shows an important staining associated with poly-lobed nuclei cells, likely to be neutrophils. In some areas, corresponding to most recently formed thrombus, fibrin and erythrocytes show an intense positivity, which may also participate in TRX release by the luminal part of the thrombus. Since TRX is released from cells in response to oxidative stress, we analysed
Discussion
AAA result from atherothrombotic complications in an infrarenal segment of the aorta, leading to a permanent arterial dilatation associated with proteolytic injury of the media. In contrast to stenosing evolution of atherothrombosis such as in carotid, femoral or coronary arteries, AAA presents an outward progression due to the weakening of the media as a consequence of extracellular matrix proteolysis and smooth muscle cell rarefaction. The formation of a luminal thrombus may be considered as
Acknowledgements
The paper have been supported by the European Community, FAD project (FP-7, HEALTH F2-2008-200647), the Spanish Ministerio de Ciencia y Tecnología (SAF2007/63648), (SAF2010-21852, SAF 2007-60896) HF2007-0120, Fundacion Ramon Areces, CAM (S2006/GEN-0247), Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Redes RECAVA (RD06/0014/0035) (Programa Miguel Servet to L.M.B.-C.) and EUS2008-03565. TJ was supported by grants from the Nouvelle Société Française d’Athérosclérose and Fondation
References (30)
- et al.
Plasma thioredoxin levels in patients with unstable angina
Int J Cardiol
(2005) - et al.
Plasma thioredoxin levels and platelet aggregability in patients with acute myocardial infarction
Am Heart J
(2003) - et al.
Thioredoxin in coronary culprit lesions: possible relationship to oxidative stress and intraplaque hemorrhage
Atherosclerosis
(2008) - et al.
The validity of ultrasonographic scanning as screening method for abdominal aortic aneurysm
Eur J Vasc Endovasc Surg
(1999) - et al.
Low plasma levels of HSP70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation
Atherosclerosis
(2007) - et al.
Role of leukocyte elastase in preventing cellular re-colonization of the mural thrombus
Am J Pathol
(2004) - et al.
Thioredoxin-linked peroxidase from human red blood cell: evidence for the existence of thioredoxin and thioredoxin reductase in human red blood cell
Biochem Biophys Res Commun
(1995) - et al.
Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway
J Biol Chem
(1992) - et al.
Demonstration of the interaction of thioredoxin with p40phox, a phagocyte oxidase component, using a yeast two-hybrid system
Immunol Lett
(1999) - et al.
Extracellular human thioredoxin-1 inhibits lipopolysaccharide-induced interleukin-1beta expression in human monocyte-derived macrophages
J Biol Chem
(2005)
Human thioredoxin-1 ameliorates experimental murine colitis in association with suppressed macrophage inhibitory factor production
Gastroenterology
Macrophage migration inhibitory factor is associated with aneurysmal expansion
J Vasc Surg
Effect of blocking platelet activation with AZD6140 on development of abdominal aortic aneurysm in a rat aneurysmal model
J Vasc Surg
Vascular surgical procedures in Denmark 1996–2004 (Karkirurgiske procedurer i Danmark 1996–2004)
Ugeskr Laeger
Final 12-year follow-up of surgery versus surveillance in the UK Small Aneurysm Trial
Br J Surg
Cited by (40)
Thioredoxin a novel biomarker of post-injury sepsis
2017, Free Radical Biology and MedicineCitation Excerpt :Thioredoxin is a key intracellular endogenous protein released into plasma in response to oxidative stress and inflammation [4,5]. This redox protein regulates several central inflammatory processes activated after trauma [4,5] and studies have shown increased plasma-TRX in critical illness involving significant inflammation [6,15–17]. Furthermore, increased plasma-TRX levels are seen in septic patients [7–9].
Thioredoxin-1/peroxiredoxin-1 as sensors of oxidative stress mediated by NADPH oxidase activity in atherosclerosis
2015, Free Radical Biology and MedicineCitation Excerpt :In this respect, circulating TRX-1 is elevated in patients with oxidative stress-associated chronic clinical conditions such as unstable angina [11,12]. In two recent studies, we have described both TRX-1 and PRX-1 as novel circulating biomarkers of AAA pathogenesis and evolution [14,32]. Furthermore, circulating TRX-1 and PRX-1 levels have been previously associated with other markers of oxidative stress (e.g., myeloperoxidase, 8-OHdG) in different pathologies [14,33].
Reduced Levels of Selenium and Thioredoxin Reductase in the Thoracic Aorta Could Contribute to Aneurysm Formation in Patients with Marfan Syndrome
2023, International Journal of Molecular Sciences