Esculetin reverses histone H2A/H2B ubiquitination, H3 dimethylation, acetylation and phosphorylation in preventing type 2 diabetic cardiomyopathy

Post translational histone modifications (PTHMs) play a pivotal role in pathogenesis of diabetic complications. Esculetin is reported to prevent glomerulosclerosis by reversing PTHMs in diabetic rats, but until now its cardioprotective role is unexplored. Hence, the present study aimed to investigate the effect of esculetin on diabetic cardiomyopathy (DCM) and its associated PTHMs. Insulin resistance (IR) and type 2 diabetic rats' heart had augmented permissive PTHMs which contributed to DCM. Besides this, for the first time we have demonstrated increased histone H2AK119Ub and H2BK120Ub levels in DCM. Esculetin treatment reduced metabolic alterations, hypertension, cardiomyocytes hypertrophy, and fibrosis in the diabetic heart. In addition, esculetin attenuated alteration in the renin-angiotensin system, oxidative stress (Keap1) and cell proliferation (Ki67); thus preventing DCM. Remarkably, esculetin treatment restored normal level of permissive PTHMs and H2A/H2B ubiquitination in IR and diabetic heart which might be the basic mechanism behind its cardioprotective role.