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

Ming-Horng Tsai; Chiang-Wen Lee; Lee-Fen Hsu; Shu-Yu Li; Yao-Chang Chiang; Ming-Hsueh Lee; Chun-Han Chen; Hwey-Fang Liang; Jia-Mei How; Pey-Jium Chang; Ching-Mei Wu; I-Ta Lee

doi:10.1016/j.redox.2017.02.019

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

Redox Biol. 2017 Aug:12:377-388. doi: 10.1016/j.redox.2017.02.019. Epub 2017 Mar 1.

Authors

Ming-Horng Tsai¹, Chiang-Wen Lee², Lee-Fen Hsu³, Shu-Yu Li⁴, Yao-Chang Chiang⁵, Ming-Hsueh Lee⁶, Chun-Han Chen⁷, Hwey-Fang Liang⁸, Jia-Mei How⁹, Pey-Jium Chang¹⁰, Ching-Mei Wu¹¹, I-Ta Lee¹²

Affiliations

¹ 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.
² 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.
³ Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi Campus, Chiayi, Taiwan.
⁴ Department of Pharmacy, College of Pharmacy & Health Care, Tajen University, Taiwan.
⁵ Center for Drug Abuse and Addiction, China Medical University Hospital, China Medical University, Taichung, Taiwan.
⁶ Division of Neurosurgery, Department of Surgery, Chang Gung Memorial Hospital, Chia-Yi 61363, Taiwan.
⁷ Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan.
⁸ Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan.
⁹ School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan.
¹⁰ Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Taiwan.
¹¹ Department of Sports Medicine, College of Health Care, China Medical University, Taichung, Taiwan.
¹² 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.

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 p47^phox, 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 p47^phox translocation 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.

Keywords: Angiotensin II; Carbon monoxide; Human aortic smooth muscle cell; Inflammation; Matrix metallopeptidase-9.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Angiotensin II / pharmacology*
Aorta
Cell Movement / drug effects
Gene Expression Regulation / drug effects
Humans
Interleukin-6 / metabolism*
Matrix Metalloproteinase 9 / metabolism*
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / drug effects*
Muscle, Smooth, Vascular / metabolism
Myocytes, Smooth Muscle / cytology
Myocytes, Smooth Muscle / drug effects
Myocytes, Smooth Muscle / metabolism
NADPH Oxidases / metabolism
Organometallic Compounds / pharmacology*
Oxidative Stress / drug effects
Reactive Oxygen Species / metabolism*
Signal Transduction / drug effects

Substances

Interleukin-6
Organometallic Compounds
Reactive Oxygen Species
tricarbonyldichlororuthenium (II) dimer
Angiotensin II
NADPH Oxidases
Matrix Metalloproteinase 9