Cathepsin K knockout mitigates high-fat diet-induced cardiac hypertrophy and contractile dysfunction.
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.
Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, School of Pharmacy, College of Health Sciences, Laramie, Wyoming, USA.
Yinan
Y
Hua
Yingmei
Y
Zhang
Julia
J
Dolence
Guo-Ping
GP
Shi
Jun
J
Ren
Sreejayan
S
Nair
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000503:physiopathology*; D056657:Cathepsin K / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D018149:Glucose Intolerance / Q000235:genetics / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D019308:Palmitic Acid; D045304:Cytochromes c; D051057:Proto-Oncogene Proteins c-akt; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D002118:Calcium