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

• Published in: PloS one 2016-03, Vol.11 (3), p.e0151845-e0151845
• Main Authors: Shang, Fenqing, Zhang, Jiao, Li, Zhao, Zhang, Jin, Yin, Yanjun, Wang, Yaqiong, Marin, Traci L, Gongol, Brendan, Xiao, Han, Zhang, You-Yi, Chen, Zhen, Shyy, John Y-J, Lei, Ting
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; ADP-ribosylation; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - drug effects; AMP-Activated Protein Kinases - physiology; Angiotensin; Angiotensin II; Animal models; Animals; Antidiabetics; Benzimidazoles - pharmacology; Benzoates - pharmacology; Biology and Life Sciences; Blotting, Western; Cardiotonic Agents - pharmacology; Care and treatment; Cells, Cultured; Diabetes mellitus; Dosage and administration; Endothelial cells; Endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Glipizide - pharmacology; Homology; Humans; Hyperglycemia; Hypertension; Kinases; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Mating; Medicine and Health Sciences; Metformin; Metformin - pharmacology; Metoprolol; Metoprolol - pharmacology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutants; Nitric oxide; Nitric Oxide - metabolism; Nitric-oxide synthase; Oxidative stress; Phosphorylation; Physical Sciences; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - drug effects; Poly(ADP-ribose) Polymerases - metabolism; Poly(ADP-ribose) Polymerases - physiology; Rats, Inbred SHR; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Ribose; Rodents; Science; SIRT1 protein; Telmisartan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0151845

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.