Cathepsin K Knockout Mitigates High-Fat Diet–Induced Cardiac Hypertrophy and Contractile Dysfunction

Abstract

The 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.

Cathepsin K osteoporosis trials, pycnodysostosis and mouse deficiency models: Commonalities and differences

“…Animal models have shown that CatK deficiency has a beneficial effect on age and obesity-related cardiac hypertrophy and atherosclerosis. [109][110][111][112][113] Currently, there are no known studies to confirm this finding in pycnodysostosis patients.…”

“…[111] Furthermore, it has been shown that the ablation of this protease mitigated pressure overload-induced cardiac hypertrophy, obesity-associated cardiac hypertrophy, and contractile dysfunctions as well as prevented ageing-associated cardiac anomalies without altering cardiac fibrosis. [112,113] Little is known about the functions of CatK in the brain. The protease has been implicated in endorphin degradation and linked to schizophrenia.…”

Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia

“…Previous studies using CatK knockout animals provide evidence that CatK specifically mediates biological effects in cellular events 21,30 . In line with these findings, our results showed that blood flow recovery and capillary formation following hindlimb ischaemia were substantially impaired in CatK À / À mice.…”

Cathepsins in heart disease–chewing on the heartache?

“…Loss of cathepsin K alleviates both pressure overload-induced and high-fat dietinduced cardiac hypertrophy, likely through the inhibition of mammalian target of rapamycin (mTOR) and ERK pathways (13,14). On the contrary, several other cathepsins were found to be cardioprotective.…”