Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade

Fenqing Shang,Ting Lei,Zhen Chen,Yaqiong Wang,John Y-J Shyy,Brendan Gongol,Traci L Marin,Yanjun Yin,You-Yi Zhang,Jin Zhang,Han Xiao,Jiao Zhang,Zhao Li

doi:10.1371/journal.pone.0151845

Abstract

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.

Highlights

Endothelial function is impaired under pathophysiological conditions such as hyperglycemia and hypertension, in part because of an imbalanced redox state
Given that AMPK activity is inhibited under hyperglycemia and a high level of angiotensin II (Ang II), both known to augment oxidative stress in endothelial cells (ECs) [21,22], we first sought to test whether phosphorylation of poly (ADP-ribose) polymerase 1 (PARP1) Ser-177 was decreased under these conditions with the use of the newly developed anti-phospho-PARP1
We demonstrated for the first time that AMPK phosphorylation of PARP1 Ser-177 in vivo, which contributes to the endothelial protection in the context of anti-hypertensive and anti-diabetic drugs

Summary

Introduction

Endothelial function is impaired under pathophysiological conditions such as hyperglycemia and hypertension, in part because of an imbalanced redox state. Metformin and Telmisartan Activates AMPK-PARP1 maintenance of genome stability. Mild activation of PARP1 can be protective and promote cell survival, excessive and sustained oxidative stress can cause overactivation of PARP1, which escalates the oxidative stress and stimulates pro-inflammatory and necrotic responses [1]. At the expense of NAD+, PARP1 synthesizes PAR for "PARylation" of itself and other nuclear and cytoplasmic proteins, which depletes cellular NAD+ and ATP and activates transcription factors such as NF-κB and AP-1 and inactivates SIRT1 deacetylase [2,3,4,5]. In addition to NF-κB activation, PARP1 exerts its pro-inflammatory effect by binding to the B-cell lymphoma 6 (Bcl-6) intron 1 to suppress the expression of Bcl-6 protein [6]

Methods

Results

Conclusion