Fibrosis in endstage human heart failure: Severe changes in collagen metabolism and MMP/TIMP profiles
Introduction
The main collagens in the myocardial extracellular matrix (ECM) are type I (50–85%) and type III (10–45%) collagens [1]. These fibrillar collagens are secreted into the extracellular space as procollagens with large propeptides at both ends. After secretion, the propeptides are cleaved by specific tissue endopeptidases and the collagen molecules aggregate to form the fibril. They are stabilized by intra- and intermolecular cross-linking [2]. The propeptides are differentiated into either N-terminal propeptides (PINP and PIIINP) or carboxyterminal telopeptides (ICTP) or aminoterminal telopeptides (IIINTP). PINP and PIIINP characterize the newly synthesized type I and III collagens, IIINTP is a marker of cross-linked mature collagen III, whereas ICTP detects a degradation product of cross-linked type I collagen [3], [4].
Collagens are extremely stable and highly resistant to degradation by all proteinases except for matrix metalloproteinases (MMP). MMPs are known modulators of myocardial remodeling underlying heart failure progression (reviewed in [5]). The interplay and balance of MMPs and their tissue inhibitors (TIMP) determine the maintenance of interstitial tissue homeostasis.
Different specific proteolysis/antiproteolysis changes of the ECM were reported in various heart diseases [6], [7], [8], [9], [10], however, more data are needed to substantiate the consistency of these results, especially in human patients. Furthermore, it appears to be interesting to correlate changes in MMP/TIMP concentrations with alterations of the collagen metabolism.
The circulating collagen propeptides are commonly used as markers of collagen metabolism. Serum appearance of collagen I and III fragments were demonstrated after myocardial infarction, hypertrophic cardiomyopathy and other heart diseases [11], [12], [13], [14], [15]. However, only a direct examination of cardiac tissues represents the most reliable method for the evaluation of collagen metabolism and the quantification of myocardial fibrosis [16] because collagen markers in serum may be elevated due to liver fibrosis, systemic sclerosis, cancer, bone and joint diseases, atherosclerosis and other pathologies [17], [18], [19], [20], [21]. There is, however, very limited information concerning changes of collagen metabolism in failing human hearts.
Several factors such as TGFβ, angiotensin II and others regulate myocardial fibrosis [22], [23]. Fibroblast growth factor 1 (FGF1) and 2 (FGF2), atrial natriuretic peptide (ANP), activin A and fibrosin are cytokines with many important functions including anti- and profibrogenic activity and the ability to activate different types of cells. It is therefore reasonable to hypothesize that these factors may also be involved in myocardial ECM remodeling.
There are no comprehensive studies comparing changes in collagen metabolism, the levels of MMPs and TIMPs and the degree of cytokine expression in failing human hearts with different cardiac diseases. Therefore, we tested the hypothesis that each pathogenetic entity possesses its own pattern of proteolysis/antiproteolysis, but that the collagen turnover is similar in all patients finally resulting in remodeling of the ECM and fibrosis. Similarly, we postulated that changes in collagen metabolism, the levels of MMPs and TIMPs and the degree of cytokine expression interrelate with each other. This process of myocardial remodeling reduces cardiac compliance and significantly contributes to diastolic dysfunction in the failing heart.
Section snippets
Patients
Left ventricular (LV) samples were collected from the explanted hearts of patients who underwent orthotopic transplantation because of endstage heart failure. All patients were severely symptomatic (NYHA grade IV). Patients either had normal coronary arteries with histologically proven MYO (n = 6) according to the Dallas criteria, or were diagnosed as idiopathic DCM (n = 6), or ischemic ICM (n = 7) cardiomyopathy. The duration of myocarditis was 3.5 ± 1.8 years. Clinical data are summarized in Table 1.
Collagens I and III
Collagens I and III were used as indicators of fibrosis and were determined separately; the typical localization is shown in Fig. 1 and in Fig. S1. It is evident that the amount of collagen III in all tissues was much higher than that of collagen I, with the exception of collagen I in ICM-BZ which was similar to collagen III. Vimentin immunolabeling was used as a marker of fibroblasts. As shown in Fig. 2, as compared with control, the number of vimentin-positive cells were apparently increased
Discussion
The major results of the study are the following: All values for collagens and markers of collagen metabolism, as well as MMPs and TIMPs are low in control tissue and all including the markers for newly synthetized and mature collagens are elevated in failing hearts. In addition, the failing myocardium is characterized by increased numbers of fibroblasts and TGF-ß1-positive cells. Based on these findings, a schematic representation of different mechanisms involving ECM cells, MMPs, TIMPs, and
Conclusions
The present study shows that although different degrees of severity of collagen metabolism, MMP/TIMP imbalance and cytokine expression in diverse forms of HF are present, the end product is collagen deposition. In addition, the failing myocardium is characterized by discordant changes in the content of collagen types I and III. This observation implies that multiple mechanisms acting alone or in concert are active in fibrosis development. This finding is important because the properties of the
Acknowledgments
We thank Dr. Svetlana Oustanina and Dr. Kerstin Troidl for their expert technical assistance in performing RT-PCR. This study was supported by grants from the Max-Planck-Gesellschaft, München, Germany, for cooperation with the Kerckhoff Clinic, Bad Nauheim, Germany (PFOR404 to V.P.; PFOR371 to V.P. and S.K.; and PFOR401 to S.H., J.S and S.K).
The authors of this manuscript have certified that they comply with the principles of ethical publishing in the International Journal of Cardiology [52].
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