Inhibition of CAV1 attenuates diabetic cardiomyopathy through reducing ferroptosis via activating NRF2/GCLC signaling pathway

Background: Diabetic cardiomyopathy (DCM), a prevalent complication of diabetes, is a major cause of heart failure and death among patients with diabetes. However, the pathological mechanisms underlying the development of DCM remain unclear. This study aims to investigate the role and underlying mechanisms of caveolin-1 (CAV1) in DCM. Methods: DCM model was established in vivo through intraperitoneal injection of streptozotocin in mice and in vitro through high-glucose (HG) treatment in neonatal rat ventricular myocytes (NRVMs). CAV1-knockout (CAV1-KO) and overexpression (by injecting adeno-associated virus 9 (AAV9) encoding CAV1) mice were utilized to explore the role of CAV1 in DCM. Nuclear factor erythroid 2-related factor 2 (NRF2)-KO and AAV9-NRF2 mice and ML385 (an NRF2 inhibitor) were used to investigate the effect of NRF2 on DCM. Results: CAV1 expression was significantly increased in the cardiac tissues of diabetic mice and HG-treated NRVMs. CAV1 deficiency significantly alleviated diabetes-induced myocardial hypertrophy, fibrosis, abnormal mitochondria, excessive reactive oxygen species production, and ferroptosis. Conversely, cardiac-specific overexpression of CAV1 exacerbated cardiac dysfunction and myocardial histological abnormalities caused by diabetes. Mechanistically, CAV1 directly bound to NRF2 and inhibited its nuclear translocation, reducing the transcription of glutamate cysteine ligase catalytic subunit (GCLC), accumulating excess peroxide, and inducing ferroptosis and myocardial injury. Conclusion: CAV1 exacerbates the progression of DCM by suppressing the NRF2/GCLC pathway, suggesting that targeting CAV1 is a potential therapeutic approach for DCM.