title: Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension.
abstract: The cardioprotective benefits of aldehyde dehydrogenase 2 (ALDH2) are well established, although the regulatory role of ALDH2 in vascular remodeling in pulmonary arterial hypertension (PAH) is largely unknown. ALDH2 potently regulates the metabolism of aldehydes such as 4-hydroxynonenal (4-HNE), the endogenous product of lipid peroxidation. Thus, we hypothesized that ALDH2 ameliorates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) by inhibiting 4-HNE accumulation and regulating downstream signaling pathways, thereby ameliorating pulmonary vascular remodeling. We found that low concentrations of 4-HNE (0.1 and 1μM) stimulated cell proliferation by enhancing cyclin D1 and c-Myc expression in primary HPASMCs. Low 4-HNE concentrations also enhanced cell migration by activating the nuclear factor kappa B (NF-κB) signaling pathway, thereby regulating matrix metalloprotein (MMP)-9 and MMP2 expression in vitro. In vivo, Alda-1, an ALDH2 agonist, significantly stimulated ALDH2 activity, reducing elevated 4-HNE and malondialdehyde levels and right ventricular systolic pressure in a monocrotaline-induced PAH animal model to the level of control animals. Our findings indicate that 4-HNE plays an important role in the abnormal proliferation and migration of HPASMCs, and that ALDH2 activation can attenuate 4-HNE-induced PASMC proliferation and migration, possibly by regulating NF-κB activation, in turn ameliorating vascular remodeling in PAH. This mechanism might reflect a new molecular target for treating PAH.
authors.affiliation: Life Science Institute, Jinzhou Medical University, Jinzhou, Liaoning 121000, PR China. Electronic address: 5xu5_888@163.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Physiology, Jinzhou Medical University, Jinzhou, Liaoning 121000, PR China.
authors.forename: Shuangyue
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Physiology, Jinzhou Medical University, Jinzhou, Liaoning 121000, PR China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Ma
authors.affiliation: College of Economics and Management, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Physiology and Pathophysiology, Capital Medical University, School of Basic Medical Sciences, Beijing 100069, PR China.
authors.forename: Zhifei
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Jinzhou Medical University, Jinzhou, Liaoning 121000, PR China. Electronic address: aimeiwang@lnmu.edu.com.
authors.forename: Aimei
authors.initials: A
authors.lastname: Wang
mesh_terms: D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D000447:Aldehydes / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000037:antagonists & inhibitors / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016686:Monocrotaline; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D000447:Aldehydes; D000959:Antihypertensive Agents; D001549:Benzamides; D052117:Benzodioxoles; C530106:Ccnd1 protein, rat; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1; D008315:Malondialdehyde; D016686:Monocrotaline; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat; C027576:4-hydroxy-2-nonenal
keywords: 4-hydroxynonenal; Alda-1; Aldehyde dehydrogenase 2; NF-κB; Oxidative stress; Pulmonary arterial hypertension