Diabetic cardiomyopathy (DCM), characterized by myocardial hypertrophy and fibrosis, is a severe complication of diabetes. Activation of Yes-associated protein (Yap) has been implicated in myocardial remodeling and cardiac dysfunction. This study aimed to elucidate the role and underlying molecular mechanisms of Yap in DCM. Yap expression was evaluated in mice with type 2 diabetes mellitus (T2DM) and in neonatal rat cardiomyocytes (NRCMs) treated with high glucose (HG) or HG + palmitic acid (PA). Adeno-associated virus transfection, adenovirus infection, and a transgenic mouse model were used to modulate Yap expression both in vivo and in vitro. RNA sequencing and miRNA sequencing were used to identify Yap’s downstream targets and related mechanisms. Functional assays, including assessment of molecular markers, cell morphology, and echocardiography, were conducted to evaluate cardiomyocyte hypertrophy and fibrosis. Results showed that Yap expression was elevated in HG or HG+PA-treated NRCMs and hearts of T2DM mice, promoting myocardial hypertrophy and fibrosis. Inhibition of Yap reduced cardiomyocyte cross-sectional area, collagen deposition, and levels of hypertrophy markers atrial natriuretic peptide and β-myosin heavy chain. RNA sequencing identified Sirt1 as a downstream target of Yap. Bioinformatics analysis indicated that Yap positively regulated miR-22-3p, which in turn inhibited Sirt1. Yap inhibition increased Sirt1 expression, alleviating myocardial remodeling. Conversely, Sirt1 knockdown reversed the protective effects of Yap inhibition, exacerbating hypertrophy and fibrosis. In conclusion, Yap promotes the progression of DCM by upregulating miR-22-3p expression and suppressing Sirt1 expression. Therapeutically targeting the newly identified Yap–miR-22-3p–Sirt1 axis could mitigate multiple aspects of diabetic cardiac remodeling.
- Diabetic cardiomyopathy (DCM) describes the abnormality of myocardial structure and function caused by diabetes, and Yes-associated protein (Yap) is linked to various cardiovascular diseases, modulating remodeling and cardiac function in hearts, but its role in DCM is unclear.
- How Yap affects myocardial structure and function in mice with type 2 diabetes mellitus and the underlying pathways were investigated.
- High glucose or high glucose plus palmitic acid levels enhance Yap activity, thereby promoting miR-22-3p expression and inhibiting sirtuin 1 (Sirt1) expression. The Yap–miR-22-3p–Sirt1 axis plays critical roles in the cause of DCM.
- The molecular pathways investigated offer promising targets for therapeutic intervention against DCM and provide new insights into the development of innovative treatment strategies to combat cardiac dysfunction in patients with diabetes.
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