title: Cathepsin K knockout alleviates aging-induced cardiac dysfunction.
abstract: Aging is a major risk factor for cardiovascular disease. It has previously been shown that protein levels of cathepsin K, a lysosomal cysteine protease, are elevated in the failing heart and that genetic ablation of cathepsin K protects against pressure overload-induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that cathepsin K knockout alleviates age-dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca(2+) properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura-2 technique, immunohistochemistry, Western blot and TUNEL staining, respectively. Aged (24-month-old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thickness, myocyte cross-sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca(2+) release compared to young (6-month-old) mice, which were attenuated in the cathepsin K knockout mice. Cellular markers of senescence, including cardiac lipofuscin, p21 and p16, were lower in the aged-cathepsin K knockout mice compared to their wild-type counterpart. Mechanistically, cathepsin K knockout mice attenuated an age-induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis-inducing factor (AIF). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of cathepsin K blocked the doxorubicin-induced translocation of AIF from the mitochondria to the nuclei. Collectively, these results suggest that cathepsin K knockout attenuates age-related decline in cardiac function via suppressing caspase-dependent and caspase-independent apoptosis.
authors.affiliation: Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, School of Pharmacy, College of Health Sciences, Laramie, WY, 82071, USA.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Hua
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Robinson
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Cao
authors.forename: Guo-Ping
authors.initials: GP
authors.lastname: Shi
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.forename: Sreejayan
authors.initials: S
authors.lastname: Nair
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D006332:Cardiomegaly / Q000235:genetics*; D020169:Caspases / Q000378:metabolism; D056657:Cathepsin K / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D009200:Myocardial Contraction / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism*
chemical_list: D020169:Caspases; D056657:Cathepsin K
keywords: aging; apoptosis; cardiac function; cardiac hypertrophy; cardiac remodeling; cathepsin K