cytochrome-c-t and Glucose-Intolerance

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.

Topics: Animals; Apoptosis; Calcium; Cardiomegaly; Cathepsin K; Cell Line; Cytochromes c; Cytoplasm; Diet, High-Fat; Enzyme Inhibitors; Gene Silencing; Glucose Intolerance; Hypoglycemic Agents; Insulin; Lysosomes; Male; Mice; Mice, Knockout; Mitochondria; Myocardial Contraction; Myocytes, Cardiac; Obesity; Palmitic Acid; Phosphorylation; Proto-Oncogene Proteins c-akt; Ventricular Remodeling

To examine apoptotic markers in serum of subjects with diabetes and impaired glucose tolerance (IGT). Serum levels of p53 and cytochrome c, regulator molecules for apoptosis, were measured in subjects with type 2 diabetes, subjects with IGT and healthy controls.. Forty one subjects with type 2 diabetes, 27 with IGT and 27 healthy volunteers were included in the study. Serum level of cytochrome c and p53 were measured with competitive ELISA.. Serum levels of p53 were lower in the group of subjects with type 2 diabetes (085+/-0.39 U/ml) than in controls (1.09+/-0.49 U/ml) (P < 0.05) and in the subjects with IGT (0.98+/-0.37 U/ml) (P < 0.05). There was no significant difference between the group with IGT and controls. Also, there was no difference for serum level of cytochrome c among the groups. In the group of subjects with type 2 diabetes, serum level of cytochrome c was mildly correlated with HbA1c (r:0.39, P < 0.05).. The present study shows that the serum level of p53 is lower in the patients with type 2 diabetes than in controls or in subjects with IGT. No difference was seen among the the groups for the serum level of cytochrome c.

Topics: Adult; Aged; Case-Control Studies; Cytochromes c; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Glucose Intolerance; Humans; Male; Middle Aged; Tumor Suppressor Protein p53