Author + information
- Wolfram-Hubertus Zimmermann, MD∗ ()
- Institute of Pharmacology, Heart Research Center Göttingen, University Medical Center Göttingen, Germany; and the DZHK (German Center for Cardiovascular Research), Göttingen, Germany
- ↵∗Reprint requests and correspondence:
Dr. Wolfram-Hubertus Zimmermann, Institute of Pharmacology, Heart Research Center Göttingen, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.
Proteolytic cleavage of extracellular matrix (ECM) proteins is a highly (dys)regulated biological process in the healthy and diseased heart (1). ECM cleavage products, such as the N-terminal fragment of type I collagen (procollagen I N-terminal peptide), the carboxy-terminal telopeptide of type I collagen, and the N-terminal fragment of type III collagen, are frequently used as biomarkers for collagen type I synthesis, collagen type I degradation, and collagen type III synthesis, respectively. A prominent example is detection of elevated carboxy-terminal telopeptide of type I collagen blood levels in patients with particularly poor outcomes in EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) (2). Many additional ECM and apparently fibrosis-associated circulating biomarkers have been introduced, but their predictive value in clinical trials remains, for the most part, elusive (3). More recently, it has become apparent that ECM cleavage products may be more than just innocent bystanders in myocardial remodeling processes, because some appear to encompass disease-modifying biological activity. For those, the term matricryptins has been introduced (4). Matricryptins are cleaved from various ECM proteins, including collagens, elastin, and hyaluronan.
By far the most abundant ECM proteins in the heart, collagen types I and III exhibit intricate structural and signaling functions (5). Post-myocardial infarction (MI) collagen deposition helps to maintain the mechanical strength of the affected ventricular wall. It is, however, important to realize that the process of post-infarct wound healing must be fine-tuned to avoid excessive fibrosis or dilation because of insufficient mechanical stability. Ventricular fibrosis is, for the most part, irreversible and will progressively result in weakening of myocardial performance and an increased incidence of electrophysiological re-entry. Finally, a balance of ECM production and turnover is essential in possibly all disease processes affecting the heart.
Matrix metalloproteinase (MMP)-2, also known as gelatinase A, and MMP-9 (or gelatinase B) are key collagen-degrading enzymes in the heart with broad and partially overlapping substrate specificity (6). MMP-9 is strongly up-regulated in the acutely infarcted heart (7) and secreted predominantly by activated macrophages (6). Also, in mouse models, MMP-9 is similarly up-regulated acutely after MI and correlates directly with left ventricular (LV) dysfunction; interestingly, MMP-9–deficient mice exhibited better LV function post-MI (8).
In this issue of the Journal, Lindsey et al. (9) identified a previously unrecognized MMP-2 and -9 cleavage site within the collagen type I protein. Cleavage at this site resulted in release of an 18-kD peptide fragment (C-1158/59). In a mouse model of MI, C-1158/59 was elevated markedly in infarcted, but not remote myocardium. The highest C-1158/59 abundance was observed after the acutely increased MMP-9 activity returned to baseline levels 7 days post-MI. This finding was in agreement with the observed degradation of C-1158/59 under extended exposure to MMP-9, suggesting that MMP-9, potentially together with other MMPs, on the one hand contributes to the appearance of C-1158/59 (by collagen type I cleavage), while on the other hand suppressing its biological activity (by peptide degradation) (Figure 1).
Cell culture experiments demonstrated enhanced mouse cardiac fibroblast migration and capillary formation in human umbilical vein endothelial cells in the presence of C-1158/59. Thus, the authors conceptualized that these biological activities may aid wound healing if stabilized shortly after MI. To test this hypothesis, a 15 amino acid peptide mimetic of the C-1158/59 cleavage product was synthesized and applied via osmotic mini-pumps for 7 days, starting 3 h post-MI induced by permanent occlusion of the left anterior descending coronary artery. In this proof-of-concept study, less LV dilation and collagen type I deposition (i.e., less fibrosis) with concomitantly enhanced type III collagen was observed in the C-1158/59 peptide-treated mouse cohort. The shift in collagen type I and III ratio may constitute the mechanistic underpinning for the observed preservation of LV geometry in the C-1158/59 group (Figure 1). Interestingly, enhanced capillarization without evidence for cardiomyocyte atrophy was observed in not only the infarcted but also remote myocardium. This could have further contributed to the observed advantageous wound healing processes. Finally, evidence for a pathophysiological role of endogenous C-1158/59 was provided by analyzing blood samples from patients taken 24 to 48 h after MI. Enhanced venous blood levels of C-1158/59 correlated negatively with LV filling, suggesting that therapeutic elevation of C-1158/59 could have a beneficial effect on disease progression.
Identifying a small peptide fragment with biological activity on the post-infarct tissue scarring processes is highly attractive because it offers the opportunity for biotechnological mass production and protein engineering for enhanced activity as well as specificity. It may also facilitate the discovery of new molecular entities with more favorable pharmacokinetic and pharmacodynamic properties. Lindsey et al. (9) provide the first hints for the therapeutic efficacy of C-1158/59. However, further pre-clinical data are needed to scrutinize its mode of action, timing, and dosing. Also, it will be necessary to determine long-term effects, including unwanted and off-target effects, before considering clinical trials with hard endpoints, such as time to the development of symptomatic heart failure (HF) and death from HF or associated arrhythmias.
Targeting fibroblast and endothelial function after MI for therapeutic modulation of wound healing is conceptually interesting, as it offers a new therapeutic direction in times where protection from neuro-humoral overstimulation (with beta-adrenoceptor blockers and inhibitors of the renin-angiotensin-aldosterone system) appears to have reached its maximal, but still insufficient, clinical effect. For synthetic C-1158/59, we now see preliminary proof of concept for biological and, importantly, disease-modifying activity—albeit with no long-term follow-up and limited functional data. The association of C-1158/59 blood levels with disease progression in the post-infarction setting in humans is an important observation, as it supports the validity of the mouse model in early pre-clinical studies in this line of drug development. To enhance our fundamental knowledge and inform clinical translation, additional pre-clinical studies in arguably more relevant disease models should be considered (e.g., a large animal model with ischemia-reperfusion injury). Importantly, off-target effects must be anticipated if a fundamental process such as ECM homeostasis is therapeutically targeted. Consequently, delivery methods specific to the heart and more specifically to the area of infarction may have to be developed. Myocardial gene delivery via viral vectors with cardiac tropism might solve this challenge (10).
Finally, a word of caution: we have observed many exceptionally effective innovative therapeutics in mouse models in the past decades. Few, if any, have found a clinical application. This may, in part, be due to the limited translational value of rodent models, suboptimal patient selection in early clinical trials, or lack of efficacy on top of state-of-the-art therapy. Despite this caveat and in light of the limited therapeutic options in the globally growing population of patients with HF, the data on the C-1158/59 matricryptin and the general concept of targeting the early remodeling process after MI are highly attractive. Considering the myocardial stroma cells and the myocardial stroma itself as primary targets for HF therapy promises a paradigm shift from today’s cardiomyocyte-centric approach to HF therapeutics.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Zimmermann has reported that he has no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Spinale F.G.
- Iraqi W.,
- Rossignol P.,
- Angioi M.,
- et al.
- Lopez B.,
- Gonzalez A.,
- Ravassa S.,
- et al.
- Iyer R.P.,
- Patterson N.L.,
- Fields G.B.,
- Lindsey M.L.
- Manhenke C.,
- Ueland T.,
- Jugdutt B.I.,
- et al.
- Lindsey M.L.,
- Iyer R.P.,
- Zamilpa R.,
- et al.