title: CO-releasing molecules CORM2 attenuates angiotensin II-induced human aortic smooth muscle cell migration through inhibition of ROS/IL-6 generation and matrix metalloproteinases-9 expression.
abstract: Ang II has been involved in the pathogenesis of cardiovascular diseases, and matrix metalloproteinase-9 (MMP-9) induced migration of human aortic smooth muscle cells (HASMCs) is the most common and basic pathological feature. Carbon monoxide (CO), a byproduct of heme breakdown by heme oxygenase, exerts anti-inflammatory effects in various tissues and organ systems. In the present study, we aimed to investigate the effects and underlying mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on Ang II-induced MMP-9 expression and cell migration of HASMCs. Ang II significantly up-regulated MMP-9 expression and cell migration of HASMCs, which was inhibited by transfection with siRNA of p47phox, Nox2, Nox4, p65, angiotensin II type 1 receptor (AT1R) and pretreatment with the inhibitors of NADPH oxidase, ROS, and NF-κB. In addition, Ang II also induced NADPH oxidase/ROS generation and p47phoxtranslocation from the cytosol to the membrane. Moreover, Ang II-induced oxidative stress and MMP-9-dependent cell migration were inhibited by pretreatment with CORM-2. Finally, we observed that Ang II induced IL-6 release in HASMCs via AT1R, but not AT2R, which could further caused MMP-9 secretion and cell migration. Pretreatment with CORM-2 reduced Ang II-induced IL-6 release. In conclusion, CORM-2 inhibits Ang II-induced HASMCs migration through inactivation of suppression of NADPH oxidase/ROS generation, NF-κB inactivation and IL-6/MMP-9 expression. Thus, application of CO, especially CORM-2, is a potential countermeasure to reverse the pathological changes of various cardiovascular diseases. Further effects aimed at identifying novel antioxidant and anti-inflammatory substances protective for heart and blood vessels that targeting CO and establishment of well-designed in vivo models properly evaluating the efficacy of these agents are needed.
authors.affiliation: Department of Pediatrics, Division of Neonatology and Pediatric Hematology/Oncology, Chang Gung Memorial Hospital, Yunlin, Taiwan; Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taiwan.
authors.forename: Ming-Horng
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan; Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi, Taiwan; Research Center for Industry of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan. Electronic address: cwlee@mail.cgust.edu.tw.
authors.forename: Chiang-Wen
authors.initials: CW
authors.lastname: Lee
authors.affiliation: Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan.
authors.forename: Lee-Fen
authors.initials: LF
authors.lastname: Hsu
authors.affiliation: Department of Pharmacy, College of Pharmacy & Health Care, Tajen University, Taiwan.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Li
authors.affiliation: Center for Drug Abuse and Addiction, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors.forename: Yao-Chang
authors.initials: YC
authors.lastname: Chiang
authors.affiliation: Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Chia-Yi 61363, Taiwan.
authors.forename: Ming-Hsueh
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan.
authors.forename: Chun-Han
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan.
authors.forename: Hwey-Fang
authors.initials: HF
authors.lastname: Liang
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Jia-Mei
authors.initials: JM
authors.lastname: How
authors.affiliation: Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taiwan.
authors.forename: Pey-Jium
authors.initials: PJ
authors.lastname: Chang
authors.affiliation: Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan.
authors.forename: Ching-Mei
authors.initials: CM
authors.lastname: Wu
authors.affiliation: School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung, Taiwan. Electronic address: ita0128@mail.cmu.edu.tw.
authors.forename: I-Ta
authors.initials: IT
authors.lastname: Lee
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D001011:Aorta; D002465:Cell Movement / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D009942:Organometallic Compounds; D017382:Reactive Oxygen Species; C447082:tricarbonyldichlororuthenium (II) dimer; D000804:Angiotensin II; D019255:NADPH Oxidases; D020780:Matrix Metalloproteinase 9
keywords: Angiotensin II; Carbon monoxide; Human aortic smooth muscle cell; Inflammation; Matrix metallopeptidase-9