An Yuan-Ming, Feng Han, Zhang Xing-Zhong, Cong Xin, Zhao Qian, Wu Li-Ling, Dou Dou
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China; Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, China.
Biochem Biophys Res Commun. 2017 Apr 22;486(1):178-183. doi: 10.1016/j.bbrc.2017.03.022. Epub 2017 Mar 9.
Endothelium-independent coronary vasoconstriction induced by continuous hypoxia contributes to the development of ischemic heart diseases. Acute elevation of homocysteine (Hcy) has a potent of vasodilation. The present study aims to investigate the role of Hcy in endothelium-independent hypoxic coronary vasoconstriction and its underlying mechanisms.
Vessel tension of isolated porcine coronary arteries was measured by organ chamber study and the protein expression were detected by western blot. A sustained contraction of porcine coronary artery was induced when exposed to prolonged hypoxia for more than 15 min, which was significantly reduced by Hcy in a dose-dependent manner but not affected by cysteine or N-acetyl-l-cysteine. Phosphorylated myosin light chain (MLC-p) at Ser19 was decreased when exposure to hypoxia for 15 min, and could be reversed by prolonged hypoxia for 30 and 60 min. The recovery of MLC-p at Ser19 by hypoxia for more than 30 min could be abolished by Hcy. The protein levels of phosphorylated Akt at Ser473 and phosphorylated P85 at Tyr508 were decreased by Hcy in normoxia, and were also reduced exposure to hypoxia for 15 min and then augmented by prolonged hypoxia for more than 30 min, which could be prevented by Hcy. The protein level of P110α was not affected by Hcy or prolonged hypoxia.
This study demonstrates that Hcy can ameliorate the endothelium-independent hypoxic coronary vasoconstriction, in which the inhibition of PI3K/Akt signaling pathway may be involved.
持续缺氧诱导的内皮依赖性冠状动脉血管收缩促进缺血性心脏病的发展。同型半胱氨酸（Hcy）的急性升高具有强大的血管舒张作用。本研究旨在探讨Hcy在内皮依赖性缺氧性冠状动脉血管收缩中的作用及其潜在机制。
通过器官浴槽实验测量离体猪冠状动脉的血管张力，并用蛋白质印迹法检测蛋白质表达。当猪冠状动脉暴露于长时间缺氧超过15分钟时，会诱导其持续收缩，Hcy可使其以剂量依赖性方式显著降低，但不受半胱氨酸或N-乙酰-L-半胱氨酸的影响。暴露于缺氧15分钟时，Ser19位点的磷酸化肌球蛋白轻链（MLC-p）减少，而长时间缺氧30分钟和60分钟可使其恢复。Hcy可消除缺氧30分钟以上对Ser19位点MLC-p的恢复作用。在常氧条件下，Hcy可降低Ser473位点的磷酸化Akt和Tyr508位点的磷酸化P85的蛋白水平，暴露于缺氧15分钟时其水平也降低，而长时间缺氧超过30分钟则使其升高，Hcy可阻止这种变化。P110α的蛋白水平不受Hcy或长时间缺氧的影响。
本研究表明，Hcy可改善内皮依赖性缺氧性冠状动脉血管收缩，这可能与PI3K/Akt信号通路的抑制有关。
