Zhang Ya-Xing, Xu Jing-Ting, You Xin-Chao, Wang Chen, Zhou Ke-Wen, Li Ping, Sun Peng, Wang Ling, Wang Ting-Huai
Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China.
Chin J Physiol. 2016 Feb 29;59(1):46-55. doi: 10.4077/CJP.2016.BAE365.
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.
分子氢（H₂）最近在预防氧化应激相关血管疾病方面引起了广泛关注。本研究旨在评估氢气对体外血管紧张素II（Ang II）刺激的血管平滑肌细胞（VSMCs）增殖和迁移的影响，以及对体内腹主动脉缩窄（AAC）诱导的血管肥大的影响。在给予10⁻⁷ M Ang II前30分钟添加富氢培养基（0.6~0.9 ppm），然后在Ang II刺激24小时后测定增殖和迁移指数。在AAC手术前连续一周以1 ml/100 g/天的剂量腹腔注射氢气（99.999%），并在体内持续6周。氢气在体外抑制Ang II刺激的VSMCs增殖和迁移，并改善体内AAC诱导的血管肥大。氢气处理降低了Ang II或AAC诱导的氧化应激，这表现为减少Ang II刺激的VSMCs中活性氧（ROS）的产生，抑制血管和血清丙二醛（MDA）中3-硝基酪氨酸（3-NT）的水平。氢气处理还在体外阻断了Ang II诱导的细胞外信号调节激酶1/2（ERK1/2）、p38丝裂原活化蛋白激酶（MAPK）、c-Jun氨基末端激酶（JNK）和埃兹蛋白/根蛋白/膜突蛋白（ERM）的磷酸化。综上所述，我们的研究表明氢气在体内可预防AAC诱导的血管肥大，在体外可能通过靶向ROS依赖的ERK1/2、p38 MAPK、JNK和ERM信号通路抑制Ang II诱导的VSMCs增殖和迁移。这为氢气抑制VSMCs异常增殖和迁移以及改善血管重塑疾病提供了分子基础。
