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Altered degradation of extracellular matrix in myocardial remodelling: the growing role of cathepsins and cystatins

Javier Díez
DOI: http://dx.doi.org/10.1093/cvr/cvq208 591-592 First published online: 23 June 2010

This editorial refers to ‘Cystatin C increases in cardiac injury: a role in extracellular matrix protein modulation’, by L. Xie et al., pp. 628–635, this issue.

Alterations in the heart's extracellular matrix, composed predominantly of fibrillar collagens types I and III, can contribute importantly to a structural remodelling of the myocardium that leads to ventricular dysfunction during either diastolic or systolic phases of the cardiac cycle. Collagen is a stable protein whose balanced turnover (synthesis and degradation) by cardiac fibroblasts can be lost under pathological conditions (Figure 1).1 When collagen synthesis predominates over its degradation, the resulting interstitial and perivascular accumulation of collagen will lead to fibrosis. On the contrary, when degradation of collagen predominates over its synthesis, the resulting loss of collagen will lead to the disruption of the physiological collagen scaffold.

Figure 1

General mechanisms and consequences of myocardial remodelling that occurs in hearts exposed to different types of injury. MMPs, matrix metalloproteinases; TIMPs, tissue inhibitors of MMPs; LV, left ventricular.

Among the many proteolytic enzymes present in the myocardium and involved in collagen degradation, members of the matrix metalloproteinase (MMP) family have received most attention. However, cathepsins and their inhibitors (i.e. cystatins) have been also implicated in collagen degradation. Cathepsins B, S, L, and K are cysteine proteases, which, when released from the lysosomes to the pericellular space, degrade extracellular matrix proteins such as elastin and fibrillar collagens.2 In addition, secreted cathepsins may activate pro-MMPs to active matrix-degrading enzymes.3 On the other hand, cystatins C, D, S, and SA are secretory proteins that act as the endogenous inhibitors of cathepsins.4 Cystatins are regulated by inflammatory cytokines and growth factors. For instance, it has been reported that transforming growth factor-β is a potent inducer of cystatin C in human vascular smooth muscle cells.5 At the cardiac level, it has been shown that cardiomyocytes express cathepsins that can be further synthesized and released in response to angiotensin II6 and the inflammatory cytokines interleukin-1β and tumour necrosis factor-α.7 Although cardiomyocytes have been found to express cystatin C,8 it is unclear how its synthesis and secretion is regulated by these cells.

The role of cathepsins and cystatins in cardiac pathophysiology needs yet to be elucidated. Left ventricular (LV) hypertrophy, enlargement, and dysfunction associated with myocardial fibrosis have been reported in cathepsin L-deficient mice.9 Increased cathepsin B mRNA and protein expression have been found in cardiac tissue from patients with dilated cardiomyopathy.10 On the other hand, cathepsins S and K have been found to be up-regulated in the myocardium of hypertensive humans and rats with heart failure (HF).7 Of interest, although cystatin C mRNA and protein expression were also enhanced in failing human and rat hearts, the total elastolytic and collagenolytic activities in myocardial extracts were abnormally increased.7

The article by Xie et al.11 provides new information of great interest. In fact, the authors observed that in mice with HF secondary to either chronic administration of doxorubicin or left anterior descending (LAD) coronary artery occlusion, myocardial cystatin C increased, and this alteration was associated with local inhibition of cathepsin B activity and accumulation of collagen types I and III as well as fibronectin. These findings raise the notion that the emphasis must be placed on the fine balance and regulation of both cathepsins and cystatins, with an imbalance resulting in a pathological state due to deficient or excessive degradation of collagen and other structural components of the myocardial extracellular matrix (Figure 1).

Some additional observations by Xie et al.11 also deserve to be considered. First, since the regulation of cystatin C in the remodelled myocardium is not known, the finding that an increased cystatin C concentration is detected in conditioned media from H2O2-treated rat cardiac myocytes supports that the release of this antiprotease is stimulated in conditions of cardiac oxidative stress. Secondly, the authors reported for the first time that cardiac fibroblasts express cystatin C, thus raising the prospect that besides cardiomyocytes, fibroblasts may also participate in the regulation of the balance between cathepsins and their inhibitors in the heart. This is further confirmed by the finding that transfected cardiac fibroblasts overexpressing cystatin C exhibit reduced conversion of cathepsin B proenzyme to the active form, inhibition of cathepsin B activity, and accumulation of fibronectin and collagen types I and III proteins. Thirdly, plasma cystatin C increased in HF mice treated with doxorubicin or subjected to LAD coronary occlusion. Since no evidence of kidney injury/dysfunction was observed in these animals, and since increased plasma cystatin C was associated with increased myocardial cystatin C, it is tempting to speculate that the excess of this protein in the bloodstream can be due to its cardiac spillover.

Additional questions arise, as should be the case for such a provocative study. One major question relates to the fact that beyond the extracellular matrix, a number of cytoskeletal, sarcolemmal, sarcoplasmic reticular, mitochondrial, and myofibrillar proteins are also substrates for cathepsins.2 Interestingly, work from different laboratories using a wide variety of techniques has shown that the activation of these and other proteases causes alterations of a number of specific proteins leading to subcellular remodelling and cardiac dysfunction, mechanisms which play a critical role in the transition from cardiac hypertrophy to HF.12 Therefore, the possibility exists that beside alterations in the extracellular balance of cathepsins/cystatins, changes in intracellular cathepsins may also contribute to global myocardial remodelling.

Is there any potential clinical translation of the findings by Xie et al.11? High levels of cystatin C have been reported to be associated with increased risk of LV hypertrophy13 and HF14 in hypertensive patients, these associations being independent of renal function. Furthermore, a number of clinical findings support cystatin C as a prognostic factor in patients with HF.15 Therefore, the possibility exists that beyond its clinical usefulness to evaluate glomerular filtration rate, circulating cystatin C may be useful as a mechanistic biomarker of myocardial remodelling (e.g. fibrosis) in patients with LV growth and dysfunction. This property of cystatin C may be also of interest in the field of cardiorenal syndrome, in the sense that exposure of the heart to high circulating levels of cystatin C, due to the reduction of glomerular filtration rate, may result in myocardial remodelling and thus contribute to the high prevalence of LV hypertrophy and decreased cardiac function observed in patients with chronic kidney disease.

In closing, Xie et al.11 should be congratulated for shedding new light on the added dimension of cardiac (and/or systemic) cystatin C as a potential mediator of myocardial remodelling. Nevertheless, further research is required for a better knowledge on the nature and development of myocardial injury related to this protein as well as on its usefulness for the diagnosis of cardiac remodelling and guidance for therapeutic interventions and prognosis in patients with cardiac disease.

Conflict of interest: none declared.


  • The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.


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