PMID- 31678650 OWN - NLM STAT- MEDLINE DCOM- 20200915 LR - 20200915 IS - 1879-3649 (Electronic) IS - 1537-1891 (Linking) VI - 124 DP - 2020 Jan TI - Metformin inhibited homocysteine-induced upregulation of endothelin receptors through the Sirt1/NF-kappaB signaling pathway in vascular smooth muscle cells. PG - 106613 LID - S1537-1891(19)30256-3 [pii] LID - 10.1016/j.vph.2019.106613 [doi] AB - Metformin (Met) can improve atherosclerosis (As). Abnormal endothelin receptors [including endothelin type A (ET(A)) or type B (ET(B)) receptor] in vascular smooth muscle cells (VSMCs) are involved in As. Hyperhomocysteinemia (HHcy) is an independent risk factor for As. The present study was designed to test our hypothesis that Met inhibits the upregulation of endothelin receptors induced by homocysteine (Hcy) in VSMCs. Rat superior mesenteric artery (SMA) without endothelium, as an in vitro model, was cultured in serum-free medium for 24 h in the presence of Hcy with or without Met or nicotinamide (Nic). In vivo, rats received subcutaneous injections of Hcy in the presence or absence of Met or Nic for 3 weeks. Levels of protein expression were determined by Western blotting. The contractile responses to sarafotoxin 6c (an ET(B) receptor agonist) or ET-1 (an ET(A)/ ET(B) receptor agonist) were studied using a sensitive myograph. The blood pressure of rats was measured using a noninvasive tail-cuff plethysmography method. The results showed that Met could significantly inhibit the Hcy-induced upregulation of endothelin receptors (including ET(A) and ET(B) receptor) protein expression and endothelin receptor-mediated vasoconstriction, and it recovered the Hcy-induced decrease in silent information regulator 1 (Sirt1) in a dosage-dependent manner in SMA. However, Nic (a Sirt1 inhibitor) recovered the levels of Met-inhibited endothelin receptors and acetylated p65. Furthermore, the in vivo results showed that Met not only significantly the inhibited HHcy-induced upregulation of endothelin receptors and acetylated p65 but also recovered the HHcy-induced decrease in Sirt1 in a dosage-dependent manner in SMA. In addition, Met significantly inhibited the HHcy-induced blood pressure elevation. However, these effects were reverted by Nic. In conclusion, these data demonstrated that Met inhibited the Hcy-induced increase in endothelin receptor expression by activating Sirt1 and then inhibiting NF-kappaB in VSMCs. These findings may provide insights into the mechanism underlying of Met-treated cardiovascular diseases induced by Hcy. CI - Copyright (c) 2019 Elsevier Inc. All rights reserved. FAU - Chen, Yulong AU - Chen Y AD - Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi 710021, China; School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi 710021, China. Electronic address: chenyulong.0901@stu.xjtu.edu.cn. FAU - Su, Xingli AU - Su X AD - School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi 710021, China. Electronic address: suxingli@xiyi.edu.cn. FAU - Qin, Qiaohong AU - Qin Q AD - Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi 710021, China. FAU - Yu, Yue AU - Yu Y AD - Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi 710021, China. FAU - Jia, Min AU - Jia M AD - Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi 710021, China; School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi 710021, China. FAU - Kong, Lingheng AU - Kong L AD - School of Basic and Medical Sciences, Xi'an Medical University, Xi'an, Shaanxi 710021, China. FAU - Zhang, Hongmei AU - Zhang H AD - The First Affiliated Hospital of Xi'an Medical University, Xi'an Medical University, Xi'an, Shaanxi 710077, China. FAU - Li, Huijin AU - Li H AD - Institute of Basic and Translational Medicine, Shaanxi Key Laboratory of Ischemic Cardiovascular Disease, Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University, Xi'an, Shaanxi 710021, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191031 PL - United States TA - Vascul Pharmacol JT - Vascular pharmacology JID - 101130615 RN - 0 (NF-kappa B) RN - 0 (Receptors, Endothelin) RN - 0LVT1QZ0BA (Homocysteine) RN - 9100L32L2N (Metformin) RN - EC 3.5.1.- (Sirt1 protein, mouse) RN - EC 3.5.1.- (Sirtuin 1) SB - IM MH - Animals MH - Blood Pressure/*drug effects MH - Cells, Cultured MH - Homocysteine/*toxicity MH - Male MH - Mesenteric Artery, Superior/drug effects/enzymology MH - Metformin/*pharmacology MH - Muscle, Smooth, Vascular/*drug effects/enzymology MH - Myocytes, Smooth Muscle/*drug effects/enzymology MH - NF-kappa B/*metabolism MH - Rats, Sprague-Dawley MH - Receptors, Endothelin/*metabolism MH - Signal Transduction MH - Sirtuin 1/*metabolism MH - Up-Regulation MH - Vasoconstriction/*drug effects OTO - NOTNLM OT - Endothelin receptors OT - Homocysteine OT - Metformin OT - Sirt1 EDAT- 2019/11/05 06:00 MHDA- 2020/09/17 06:00 CRDT- 2019/11/04 06:00 PHST- 2019/08/30 00:00 [received] PHST- 2019/10/21 00:00 [revised] PHST- 2019/10/30 00:00 [accepted] PHST- 2019/11/05 06:00 [pubmed] PHST- 2020/09/17 06:00 [medline] PHST- 2019/11/04 06:00 [entrez] AID - S1537-1891(19)30256-3 [pii] AID - 10.1016/j.vph.2019.106613 [doi] PST - ppublish SO - Vascul Pharmacol. 2020 Jan;124:106613. doi: 10.1016/j.vph.2019.106613. Epub 2019 Oct 31.