Hua, YinanZhang, YingmeiDolence, JuliaShi, Guo-PingRen, JunNair, Sreejayan2014-03-112013Hua, Yinan, Yingmei Zhang, Julia Dolence, Guo-Ping Shi, Jun Ren, and Sreejayan Nair. 2013. “Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction.” Diabetes 62 (2): 498-509. doi:10.2337/db12-0350. http://dx.doi.org/10.2337/db12-0350.0012-1797http://nrs.harvard.edu/urn-3:HUL.InstRepos:11879902The cysteine protease cathepsin K has been implicated in pathogenesis of cardiovascular disease. We hypothesized that ablation of cathepsin K protects against obesity-associated cardiac dysfunction. Wild-type mice fed a high-fat diet exhibited elevated heart weight, enlarged cardiomyocytes, increased left ventricular wall thickness, and decreased fractional shortening. All these changes were reconciled in cathepsin K knockout mice. Cathepsin K knockout partly reversed the impaired cardiomyocyte contractility and dysregulated calcium handling associated with high-fat diet. Additionally, cathepsin K knockout alleviated whole-body glucose intolerance and improved insulin-stimulated Akt phosphorylation in high-fat diet–fed mice. High-fat feeding increased the expression of cardiac hypertrophic proteins and apoptotic markers, which were inhibited by cathepsin K knockout. Furthermore, high-fat feeding resulted in cathepsin K release from lysosomes into the cytoplasm. In H9c2 myoblasts, silencing of cathepsin K inhibited palmitic acid–induced release of cytochrome c from mitochondria and expression of proapoptotic signaling molecules. Collectively, our data indicate that cathepsin K contributes to the development of obesity-associated cardiac hypertrophy and may represent a potential target for the treatment to obesity-associated cardiac anomalies.en-USJournal Article2014-03-1110.2337/db12-0350