Piezo1 deletion mitigates diabetic cardiomyopathy by maintaining mitochondrial dynamics via ERK/Drp1 pathway

ObjectiveIncreasing evidence highlights the critical role of Piezo1 in cardiovascular diseases, with its expression upregulated in diabetic heart. However, the involvement of Piezo1 in the pathogenesis of diabetic cardiomyopathy (DCM) remains unclear. This study aims to elucidate the regulatory role of Piezo1 in mitochondrial dynamics within the context of DCM and to investigate the underlying mechanisms.MethodsWe constructed cardiac-specific knockout of Piezo1 (Piezo1 triangle Myh6) mice. Type 1 diabetes was induced using streptozotocin (STZ) injection while type 2 diabetes was established through a high-fat diet combined with STZ. Echocardiography assessed left ventricular function, histological evaluations used HE and Masson staining to examine cardiac pathology in Piezo1fl/fl controls, Piezo1 triangle Myh6 controls, Piezo1fl/fl diabetic and Piezo1 triangle Myh6 diabetic mice. Mitochondrial function including oxygen species level, mitochondrial morphology, and respiration rate were also assessed.ResultsOur findings revealed that Piezo1 expression was upregulated in the myocardium of diabetic mice and in high-glucose-treated cells. Cardiac-specific knockout of Piezo1 improved cardiac dysfunction and ameliorated cardiac fibrosis in diabetic mice. Moreover, Piezo1 deficiency also attenuated mitochondrial impairment. Piezo1fl/fl diabetic mice exhibited increased calpain activity and excessive mitochondrial fission mediated by Drp1 and obvious reduced fusion; however, Piezo1 deficiency restored calpain levels and mitochondrial dysfunction. These observations were also corroborated in H9C2 cells and neonatal mouse cardiomyocytes. Cardiac-specific knockout of Piezo1 increased phosphorylation of Drp1 and ERK1/2 in vivo and in vitro. Piezo1 knockout or treatment with inhibitor improved mitochondrial function.ConclusionsThis study provides the first evidence that Piezo1 is elevated in DCM through the modulation of mitochondrial dynamics, which is reversed by Piezo1 deficiency. Thus, Piezo1 inhibition may provide a promising therapeutic strategy for the treatment of DCM.Graphic abstractIn cardiomyocytes of Piezo1fl/fl DCM mice, increased Ca2+ entry upregulates calpain activity, and phosphorylated level of ERK1/2 and Drp1. Therefore, increased mitochondrial fission is shown in DCM hearts. Whereas, cardiomyocyte-specific knockout of Piezo1 alleviates mitochondrial dysfunction.