Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science Pilani, Pilani Campus, Rajasthan, 333031, India.
Biomed Pharmacother. 2017 Nov;95:1461-1468. doi: 10.1016/j.biopha.2017.09.067. Epub 2017 Sep 21.
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.
在糖尿病状态下，微血管和大血管并发症是由上调的肾素血管紧张素系统（RAS）通过恶化血管生理学对病理刺激的反应。上调的 RAS 可影响靶组织的适应性机制，改变血管紧张素 II 型 1 受体（AT1）和血管紧张素 II 型 2 受体（AT2）的丰度。已经报道，这种 AT1 和 AT2 的差异调节与翻译后组蛋白修饰（PTHMs）有关。此外，最近的证据表明，秦皮素（6,7-二羟基香豆素）可逆转糖尿病心肌病和肾病中的翻译后组蛋白修饰（PTHMs）。鉴于这些证据，我们进一步进行了这项研究，以调查秦皮素在胰岛素抵抗（IR）和 2 型糖尿病（T2D）条件下进行性血管并发症中对 PTHMs 的影响。秦皮素治疗在 IR 和 T2D 条件下均可显著改善血管反应性，增加 eNOS 并降低血管细胞粘附分子 1（VCAM1）mRNA 水平，并减少大鼠胸主动脉胶原沉积。此外，IR 和 T2D 中 AT1 和 AT2 受体 mRNA 的倍数变化也被秦皮素治疗所逆转。秦皮素治疗组还逆转了组蛋白 H2B 赖氨酸 120 单泛素化（H2BK120Ub）的修饰。此外，通过秦皮素治疗，还证明了 H2BK120Ub 在 AT1a、At2、Tgfβ 和 Mcp1 启动子基因中的占有率发生了改变。总之，我们的研究结果表明，秦皮素通过修饰 H2BK120Ub 及其在 AT1、At2、Tgfβ1 和 Mcp1 启动子基因上的占有率，参与了血管紊乱的改善。
