Small molecule activator of Serca2a improves myocardial bioenergetics and lipid metabolism in diabetic mice

Background: Altered calcium homeostasis, insulin resistance, and dysregulated energy metabolism are major causes of diabetic cardiomyopathy. The expression and activity of Sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) are decreased in the diabetic heart failure. Increasing SERCA2a function reverses both systolic and diastolic dysfunction. However, the mechanisms and consequences underlying the role of SERCA2a in the diabetic failing heart are not clear yet. Objective: To examine the effect of pharmacological activation of SERCA2a on the diabetic heart. Methods and Results: To restore calcium abnormality in leptin-deficient (ob/ob) diabetic mice, we employed and contrasted two different models to elevate the restoration of SERCA2a function: 1) activation of SERCA2 with a novel allosteric agonist, CDN1163 or 2) overexpression of SERCA2a using cardiac-specific AAV9-mediated gene transfer. We demonstrate that SERCA2a activation with CDN1163 or AAV9 repressed the expression of genes involved in lipid synthesis and fatty acid oxidation in obese mice, leading to improved lipid homeostasis. Increased SERCA2a function improved mitochondrial function through elevation of mitochondrial biogenesis, mitochondrial DNA content, oxidative phosphorylation, and ATPase activity in the heart of obese mice. SERCA2a also restored mitochondrial membrane potential to normal levels in cultured H9C2 myocytes in the presence of high glucose and H2O2. SERCA2a ameliorated intracellular lipid toxicity and cell damage, possibly through the upregulation of the gene expression of antioxidant enzymes, and attenuated ROS generation by repression of NADPH oxidase in the obese heart. Furthermore, these molecular changes were paralleled by improvement in diabetes-induced diastolic dysfunction following CDN1163 activation of SERCA2a or AAV9-SERCA2a overexpression in the obese mice. Conclusion: These results suggest that calcium resolving diabetes-induced calcium dyshomeostasis by pharmacological activation of SERCA2a in obese individuals may be a highly effective therapeutic modality for treating obesity-induced diabetes. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.