esculetin and Insulin-Resistance

Micro and macro vascular complications under diabetic condition are the responses to pathological stimuli exerted by up regulated renin angiotensin system (RAS) via deteriorating vascular physiology. Up-regulated RAS could influence in the adaptive mechanisms of target tissues to alter the abundance of angiotensin II type 1 receptor (AT1) and angiotensin II type 2 receptor (AT2). Such differential regulation of AT1 and AT2 have been reported to be associated with post-translational histone modifications (PTHMs). Additionally, recent evidences provide, esculetin (6,7-dihydroxycoumarin) reverses post-translational histone modifications (PTHMs) in diabetic cardiomyopathy and nephropathy. On account of these evidences, we further pursued this study to investigate the effects of esculetin on PTHMs in progressive vascular complications under insulin resistance (IR) and type 2 diabetic (T2D) conditions. Esculetin treatment in both IR and T2D conditions substantially improved vascular reactivity, increased eNos and decreased Vcam1 mRNA levels, and reduced collagen deposition in rat thoracic aorta. Further, the fold changes in At1 and At2 receptor mRNA in IR and T2D were reversed by esculetin treatment. Modifications in histone H2B lysine 120 monoubiquitination (H2BK120Ub) were also reversed in esculetin treatment group. Further, modification in the occupancy of H2BK120Ub at At1a, At2, Tgfβ and Mcp1 promoter genes was evidenced by treatment with esculetin. Taken together, our investigation concluded with the involvement of esculetin in the amelioration of vascular perturbation by modifying H2BK120Ub along with occupancy at At1, At2, Tgfβ1 and Mcp1 promoter gene.

Topics: Acetylcholine; Angiotensin II; Animals; Aorta; Blood Vessels; Chemokine CCL2; Diabetes Mellitus, Type 2; Gene Expression Regulation; Hemodynamics; Histones; Insulin Resistance; Lysine; Muscle Relaxation; Myocardial Contraction; Promoter Regions, Genetic; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; RNA, Messenger; Transforming Growth Factor beta1; Ubiquitin; Umbelliferones

The combination of the angiotensin receptor blockers (ARBs) with other synthetic and natural molecules has been reported to have better safety profile and therapeutic efficacy in prevention of diabetes and its associated complications than their monotherapy. Driven by the aforementioned facts, this study was conceived to evaluate the potential additive effect of combination of Telmisartan and Esculetin in prevention of insulin resistance and associated cardiac fibrosis. Recently, we have reported that Esculetin prevented cardiovascular dysfunction associated with insulin resistance (IR) and type 2 diabetes. Insulin resistance was developed by high fat diet (HFD) feeding to Wistar rats. Telmisartan and Esculetin were administered at 10 mg/kg/day and 50 mg/kg/day doses (P.O, 2 weeks), respectively either alone or in combination. Plasma biochemical analyses, vascular reactivity and immunohistochemical experiments were performed to assess the beneficial effect of Telmisartan, Esculetin and their combination on insulin resistance and associated cardiac fibrosis. The study results showed that, co-administered Telmisartan and Esculetin ameliorated the pathological features like metabolic perturbation, morphometric alterations, vascular hyper responsiveness, extracellular matrix accumulation and the expression of fibronectin and TGF-β more effectively than monotherapy in HFD fed rats. Hence, the study urges us to conclude that the solution to IR and associated cardiovascular dysfunction may lie in the Telmisartan and Esculetin combination therapy.

Topics: Angiotensin II; Animals; Benzimidazoles; Benzoates; Cardiotonic Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fibrosis; Heart Diseases; Insulin Resistance; Male; Rats; Rats, Wistar; Telmisartan; Treatment Outcome; Umbelliferones; Vasoconstriction