Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade.
Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade.
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二甲双胍和替米沙坦的心血管保护作用：通过 AMPK-PARP1 级联降低 PARP1 活性
DOI：
10.1371/journal.pone.0151845
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Lei T
中科院分区：
文献类型：
--
作者：
Shang F;Zhang J;Li Z;Zhang J;Yin Y;Wang Y;Marin TL;Gongol B;Xiao H;Zhang YY;Chen Z;Shyy JY;Lei T
高血糖和高血压部分通过氧化应激激活的聚（adp -核糖）聚合酶1 （PARP1）损害内皮功能。双胍类药物和血管紧张素受体阻滞剂（ARBs）如二甲双胍和替米沙坦具有血管保护作用。我们使用培养血管内皮细胞（ECs）、糖尿病和高血压啮齿动物模型以及ampkα 2敲除小鼠，研究二甲双胍和替米沙坦是否通过amp活化蛋白激酶（AMPK）磷酸化PARP1从而抑制PARP1活性对内皮产生有益作用。结果表明，二甲双胍和替米沙坦能激活AMPK，而格列吡嗪和美托洛尔不能激活AMPK， AMPK在培养的内皮细胞和啮齿动物血管壁中磷酸化PARP1 Ser-177。磷酸化/去磷酸化PARP1突变体的实验表明，AMPK磷酸化PARP1导致PARP1活性降低和蛋白多聚（adp -核桃基）化（PARylation）减弱，但内皮型一氧化氮合酶（eNOS）活性和沉默交配型信息调控2同源物1 （SIRT1）表达增加。综上所述，本文的数据表明，双胍类药物和arb通过AMPK对PARP1的级联磷酸化来抑制ECs中PARP1的活性和蛋白PARylation，从而对血管系统产生有益的影响，从而减轻内皮功能障碍。
Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction.