title: Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade.
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.
authors.affiliation: Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Fenqing
authors.initials: F
authors.lastname: Shang
authors.affiliation: Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.|Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Li
authors.affiliation: Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Yaqiong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Cardiopulmonary Science and Anatomy, Schools of Allied Health and Medicine, Loma Linda University, Loma Linda, CA, United States of America.
authors.forename: Traci L
authors.initials: TL
authors.lastname: Marin
authors.affiliation: Departments of Cardiopulmonary Science and Anatomy, Schools of Allied Health and Medicine, Loma Linda University, Loma Linda, CA, United States of America.
authors.forename: Brendan
authors.initials: B
authors.lastname: Gongol
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
authors.forename: Han
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
authors.forename: You-Yi
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Department of Medicine, School of Medicine, University of California, San Diego, La Jolla CA, United States of America.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: John Y-J
authors.initials: JY
authors.lastname: Shyy
authors.affiliation: Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.|Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Lei
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005913:Glipizide / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D060888:Real-Time Polymerase Chain Reaction; D000077333:Telmisartan
chemical_list: D001562:Benzimidazoles; D001565:Benzoates; D002316:Cardiotonic Agents; D009569:Nitric Oxide; D008687:Metformin; C499320:PARP1 protein, human; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D055372:AMP-Activated Protein Kinases; D008790:Metoprolol; D000077333:Telmisartan; D005913:Glipizide