Hyperglycemia aggravates cardiomyocyte oxidative stress via Caveolin-1/Nrf2/Keap1 signaling axis activation

Diabetes mellitus (DM) leads to severe complications, including diabetic cardiomyopathy (DCM). Oxidative stress (OS) is a pivotal pathogenic mechanism contributes to cardiovascular disease in patients with DM. However, the relationship between DCM and OS remain unclear. This study aims to investigate the role and underlying mechanisms of caveolin-1 (Cav-1) in OS under hyperglycemia. We used neonatal rat ventricular myocytes (NRVMs) as an in vitro model to investigate the effects of proteins on high-glucose (HG) -induced OS. We used western blotting, RT-PCR, Co-IP, ROS assay, mitochondrial membrane potential detection, and Enzyme-Linked Immunosorbent Assay, with or without siRNA pretreatment, to conduct our experiments. HG stimulation increased ROS production and decreased the mitochondrial membrane potential. Additionally, we found that Cav-1 inhibited the expression of haemoxygenase-1 (Ho-1) by directly interacting with Nrf2 under HG stimulation. Treatment with Cav-1-siRNA significantly enhanced the expression level of Nrf2 and the transcription levels of antioxidant enzymes, which in turn reduced ROS production and restored mitochondrial membrane potential. Notably, Cav-1 also played a role in regulating apoptosis and CK-MB secretion induced by HG stimulation. In summary, our findings, for the first time, suggest that the Cav-1/Nrf2/Keap1 signaling pathway may be pivotal in the antioxidant system and apoptosis in response to HG stimulation. • High glucose stimulation decreased mitochondrial membrane potential. • High glucose induced Cav-1-Nrf2-Keap1 complex formation. • Cav-1-siRNA restored mitochondrial membrane potential under high glucose condition. • Cav-1/Nrf2/Keap1 axis mediated high glucose induced cardiomyocytes injury.