title: Inhibitory Effects of Hydrogen on Proliferation and Migration of Vascular Smooth Muscle Cells via Down-Regulation of Mitogen/Activated Protein Kinase and Ezrin-Radixin-Moesin Signaling Pathways.
abstract: Molecular hydrogen (H₂) has recently attracted considerable attention for the prevention of oxidative stress-related vascular diseases. The purpose of this study is to evaluate the effects of hydrogen on proliferation and migration of vascular smooth muscle cells (VSMCs) stimulated by angiotensin II (Ang II) in vitro, and on vascular hypertrophy induced by abdominal aortic coarctation (AAC) in vivo. Hydrogen-rich medium (0.6~0.9 ppm) was added 30 min before 10⁻⁷ M Ang II administration, then the proliferation and migration index were determined 24 h after Ang II stimulation. Hydrogen gas (99.999%) was given by intraperitoneal injection at the dose of 1 ml/100 g/day consecutively for one week before AAC and lasted for 6 weeks in vivo. Hydrogen inhibited proliferation and migration of VSMCs with Ang II stimulation in vitro, and improved the vascular hypertrophy induced by AAC in vivo. Treatment with hydrogen reduced Ang II- or AAC-induced oxidative stress, which was reflected by diminishing the induction of reactive oxygen species (ROS) in Ang II-stimulated VSMCs, inhibiting the levels of 3-nitrotyrosine (3-NT) in vascular and serum malondialdehyde (MDA). Hydrogen treatment also blocked Ang II-induced phosphorylation of the extracellular signal-regulated kinase1/2 (ERK1/2), p38 MAPK, c-Jun NH₂-terminal kinase (JNK) and the ezrin/radixin/moesin (ERM) in vitro. Taken together, our studies indicate that hydrogen prevents AAC-induced vascular hypertrophy in vivo, and inhibits Ang II-induced proliferation and migration of VSMCs in vitro possibly by targeting ROS-dependent ERK1/2, p38 MAPK, JNK and ERM signaling. It provides the molecular basis of hydrogen on inhibiting the abnormal proliferation and migration of VSMCs and improving vascular remodeling diseases.
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Ya-Xing
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Jing-Ting
authors.initials: JT
authors.lastname: Xu
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Xin-Chao
authors.initials: XC
authors.lastname: You
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Ke-Wen
authors.initials: KW
authors.lastname: Zhou
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Sun
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
authors.forename: Ting-Huai
authors.initials: TH
authors.lastname: Wang
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000502:physiology*; D015536:Down-Regulation; D006859:Hydrogen / Q000494:pharmacology*; D008565:Membrane Proteins / Q000502:physiology*; D008840:Microfilament Proteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D006859:Hydrogen; D008565:Membrane Proteins; D008840:Microfilament Proteins; D020928:Mitogen-Activated Protein Kinases; D000099149:Ezrin; C071058:moesin; C071776:radixin