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, Oct 04, 2015
12 Reads
  • 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
    • "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
  • Source
    • "The role of cathepsin L in cell survival was demonstrated in C. elegans in which transfection with siRNAs to this enzyme resulted in embryonic lethality [8]. Although the loss of cathepsin L expression was not lethal in mice, it was associated with severe abnormalities in the heart, brain, and skin [9] [10] [11] [12], suggesting that this enzyme may be required for cell survival and normal organ development. In agreement with this concept, we have reported that cathepsin L protects cancer cells from the cytotoxic effect of chemotherapeutic agents and its inhibition reverses drug resistance in various cancer cell lines [13]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The present investigation was undertaken to measure the relative abilities of pro-death versus pro-survival proteases in degrading each other and to determine how this might influence cellular susceptibility to death. For this, we first carried out in vitro experiments in which recombinant pro-death proteases (caspase-3 or cathepsin D) were incubated with the pro-survival protease (cathepsin L) in their respective optimal conditions and determined the effects of these reactions on enzyme integrity and activity. The results indicated that cathepsin L was able to degrade cathepsin D, which in turn cleaves caspase-3, however the later enzyme was unable to degrade any of the cathepsins. The consequences of this proteolytic sequence on cellular ability to undergo apoptosis or other types of cell death were studied in cells subjected to treatment with a specific inhibitor of cathepsin L or the corresponding siRNA. Both treatments resulted in suppression of cellular proliferation and the induction of a cell death with no detectable caspase-3 activation or DNA fragmentation, however, it was associated with increased accumulation of cathepsin D, cellular vaculolization, expression of the mannose-6-phosphate receptor, and the autophagy marker LC3-II, all of which are believed to be associated with autophagy. Genetic manipulations leading either to the gain or loss of cathepsin D expression implicated this enzyme as a key player in the switch from apoptosis to autophagy. Overall, these findings suggest that a hierarchy between pro-survival and pro-death proteases may have important consequences on cell fate.
    Biochimica et Biophysica Acta 09/2008; 1783(12):2294-300. DOI:10.1016/j.bbamcr.2008.07.027 · 4.66 Impact Factor
Show more