Stypmann, J. et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc. Natl Acad. Sci. USA 99, 6234-6239

Medizinische Klinik und Poliklinik C (Kardiologie und Angiologie), Universitätsklinikum Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2002; 99(9):6234-9. DOI: 10.1073/pnas.092637699
Source: PubMed


Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality. Progressive remodeling of the myocardium leads to increased dimensions of heart chambers. The role of intracellular proteolysis in the progressive remodeling that underlies dilated cardiomyopathy has not received much attention yet. Here, we report that the lysosomal cysteine peptidase cathepsin L (CTSL) is critical for cardiac morphology and function. One-year-old CTSL-deficient mice show significant ventricular and atrial enlargement that is associated with a comparatively small increase in relative heart weight. Interstitial fibrosis and pleomorphic nuclei were found in the myocardium of the knockout mice. By electron microscopy, CTSL-deficient cardiomyocytes contained multiple large and apparently fused lysosomes characterized by storage of electron-dense heterogeneous material. Accordingly, the assessment of left ventricular function by echocardiography revealed severely impaired myocardial contraction in the CTSL-deficient mice. In addition, echocardiographic and electrocardiographic findings to some degree point to left ventricular hypertrophy that most likely represents an adaptive response to cardiac impairment. The histomorphological and functional alterations of CTSL-deficient hearts result in valve insufficiencies. Furthermore, abnormal heart rhythms, like supraventricular tachycardia, ventricular extrasystoles, and first-degree atrioventricular block, were detected in the CTSL-deficient mice.

Download full-text


Available from: Jörg Stypmann,
  • Source
    • "Although only limited basic findings are available, the results that are available favor the notion that the cysteinyl Cats might be the best targets of drugs to prevent CVD in clinical trials. To our surprise, a few studies have reported that CatL-null mice exhibit a human cardiomyopathy-like phenotype.81,82 Therefore, several questions remain. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Until recently, the role of lysosomal cysteine protease cathepsins in intracellular protein degradation was believed to be mainly restricted to scavenging. However, recent studies have revealed nontraditional roles for cysteine protease cathepsins in the extracellular space during the development and progression of cardiovascular disease. Although the precise mechanisms are unknown, data from animal studies suggest that members of the cathepsin family, like other extracellular proteases, contribute to extracellular matrix protein remodeling and interstitial matrix degradation, as well as to cell signaling and cell apoptosis in heart disease. Inflammatory cytokines and hormones regulate the expression and secretion of cathepsins in cultured cardiovascular cells and macrophages. Serum levels of cathepsins L, S, and K and their endogenous inhibitor cystatin C may be useful predictive biomarkers in patients with coronary artery disease and cardiac disease. Furthermore, in vivo pharmacological intervention with a synthetic cathepsin inhibitor and cardiovascular drugs (including statins and angiotensin II type 1 receptor antagonists) has the potential for pharmacologic targeting of cathepsins in cardiovascular disease. This review focuses on cathepsin biology (structure, synthesis, processing, activation, secretion, activity regulation, and function) and the involvement of cysteinyl cathepsins in the pathogenesis of several heart and vessel diseases, especially with respect to their potential application as diagnostic and prognostic markers and drug targets to prevent inappropriate proteolysis in cardiovascular disease.
    08/2012; 48(2):77-85. DOI:10.4068/cmj.2012.48.2.77
  • Source
    • "Mouse Ctsl represents a well characterized, ubiquitously expressed lysosomal cysteine endopeptidase, which is synthesized as an inactive proenzyme followed by proteolytic cleavage into two chains upon arrival in lysosomes [43]. Analyses of Ctsl (−/−) mice revealed that mouse Ctsl plays a role in the hair cycle [21], epidermal proliferation [21] [44], cardiac homeostasis [45], processing of prohormones [46], glucose metabolism [47] and MHCII-mediated antigen presentation [48]. Different substrates of Ctsl have been identified including cytosolic proteins, lysosomal enzyme precursors, nuclear proteins, prohormones and proteins of the extracellular matrix [40]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: CLN7 is a polytopic lysosomal membrane glycoprotein of unknown function and is deficient in variant late infantile neuronal ceroid lipofuscinosis. Here we show that full-length CLN7 is proteolytically cleaved twice, once proximal to the used N-glycosylation sites in lumenal loop L9 and once distal to these sites. Cleavage occurs by cysteine proteases in acidic compartments and disruption of lysosomal targeting of CLN7 results in inhibition of proteolytic cleavage. The apparent molecular masses of the CLN7 fragments suggest that both cleavage sites are located within lumenal loop L9. The known disease-causing mutations, p.T294K and p.P412L, localized in lumenal loops L7 and L9, respectively, did not interfere with correct lysosomal targeting of CLN7 but enhanced its proteolytic cleavage in lysosomes. Incubation of cells with selective cysteine protease inhibitors and expression of CLN7 in gene-targeted mouse embryonic fibroblasts revealed that cathepsin L is required for one of the two proteolytic cleavage events. Our findings suggest that CLN7 is inactivated by proteolytic cleavage and that enhanced CLN7 proteolysis caused by missense mutations in selected luminal loops is associated with disease.
    Biochimica et Biophysica Acta 06/2012; 1822(10):1617-28. DOI:10.1016/j.bbadis.2012.05.015 · 4.66 Impact Factor
    • "Cathepsin L knockout mice suffer from periodic hair loss, epidermal hyperplasia, acanthosis (thickening of the prickle-cell layer of the skin), hyperkeratosis (thickening of the epidermis) and abnormal spermatogenesis (Gocheva and Joyce 2007; Roth et al. 2000; Wright et al. 2003). Older mice develop cardiomyopathy (Stypmann et al. 2002). Combined deficiency of cathepsin B and L in mice is lethal during the second to fourth postnatal week due to brain atrophy (Felbor et al. 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cathepsin L, a cysteine protease, is considered to be a potential therapeutic target in cancer treatment. Proteases are involved in the development and progression of cancer. Inhibition of activity of specific proteases may slow down cancer progression. In this review, we evaluate recent studies on the inhibition of cathepsin L in cancer. The effects of cathepsin L inhibition as a monotherapy on apoptosis and angiogenesis in cancer are ambiguous. Cathepsin L inhibition seems to reduce invasion and metastasis, but there is concern that selective cathepsin L inhibition induces compensatory activity by other cathepsins. The combination of cathepsin L inhibition with conventional chemotherapy seems to be more promising and has yielded more consistent results. Future research should be focused on the mechanisms and effects of this combination therapy.
    Life sciences 11/2009; 86(7-8):225-33. DOI:10.1016/j.lfs.2009.11.016 · 2.70 Impact Factor
Show more