{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:20:58Z","timestamp":1790742058584,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2015,2,18]],"date-time":"2015-02-18T00:00:00Z","timestamp":1424217600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"funder":[{"name":"NIH","award":["NIH P20RR016474"],"award-info":[{"award-number":["NIH P20RR016474"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2015,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>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\u2010induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that cathepsin K knockout alleviates age\u2010dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca<jats:sup>2+<\/jats:sup> properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura\u20102 technique, immunohistochemistry, Western blot and <jats:styled-content style=\"fixed-case\">TUNEL<\/jats:styled-content> staining, respectively. Aged (24\u2010month\u2010old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thickness, myocyte cross\u2010sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca<jats:sup>2+<\/jats:sup> release compared to young (6\u2010month\u2010old) 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\u2010cathepsin K knockout mice compared to their wild\u2010type counterpart. Mechanistically, cathepsin K knockout mice attenuated an age\u2010induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis\u2010inducing factor (<jats:styled-content style=\"fixed-case\">AIF<\/jats:styled-content>). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of cathepsin K blocked the doxorubicin\u2010induced translocation of <jats:styled-content style=\"fixed-case\">AIF<\/jats:styled-content> from the mitochondria to the nuclei. Collectively, these results suggest that cathepsin K knockout attenuates age\u2010related decline in cardiac function via suppressing caspase\u2010dependent and caspase\u2010independent apoptosis.<\/jats:p>","DOI":"10.1111\/acel.12276","type":"journal-article","created":{"date-parts":[[2015,2,18]],"date-time":"2015-02-18T12:34:52Z","timestamp":1424262892000},"page":"345-351","source":"Crossref","is-referenced-by-count":46,"title":["Cathepsin K knockout alleviates aging\u2010induced cardiac dysfunction"],"prefix":"10.1111","volume":"14","author":[{"given":"Yinan","family":"Hua","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Sciences &amp; Center for Cardiovascular Research and Alternative Medicine School of Pharmacy College of Health Sciences Laramie WY 82071 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J.","family":"Robinson","sequence":"additional","affiliation":[{"name":"WWAMI Medical Education College of Health Sciences University of Wyoming Laramie WY 82071 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongtao","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Mathematics Indiana University of Pennsylvania Indiana PA 15705 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guo\u2010Ping","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston MA 02115 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ren","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences &amp; Center for Cardiovascular Research and Alternative Medicine School of Pharmacy College of Health Sciences Laramie WY 82071 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sreejayan","family":"Nair","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences &amp; Center for 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