A critical role for cystathionine-β-synthase in hydrogen sulfide-mediated hypoxic relaxation of the coronary artery
A critical role for cystathionine-β-synthase in hydrogen sulfide-mediated hypoxic relaxation of the coronary artery
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DOI：
10.1016/j.vph.2017.05.004
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发表时间：
2017-08-01
影响因子：
4
通讯作者：
Ralevic, V.
中科院分区：
文献类型：
--
作者：
Donovan, J.;Wong, P. S.;Ralevic, V.
缺氧诱导的冠状动脉血管扩张通过增加缺血条件下的血流量来保护心脏，但其机制尚不完全清楚。据报道，硫化氢（H2S）是血管系统中的氧传感器/传感器。本研究旨在确定和描述H2S在冠状动脉缺氧反应中的作用，并确定H2S合成酶的作用。免疫印迹和免疫组织化学检测结果显示，猪冠状动脉中胱硫氨酸- β合成酶（CBS）、胱硫氨酸-y-裂解酶（CSE）和3-巯基丙酮酸硫转移酶（MPST）均有表达。安装动脉段进行等距张力记录；缺氧引起短暂的内皮依赖性收缩，随后是长时间的内皮非依赖性松弛。CBS抑制剂氨基乙酸酯（AOAA）降低了两个阶段的缺氧反应。CSE抑制剂dl -丙基甘氨酸（PPG）和天冬氨酸（极限MPST）单独使用没有效果，但当与AOAA一起使用时，缺氧松弛反应进一步降低。外源性H2S （Na2S和NaHS）产生浓度依赖性收缩，随后是延长的松弛。对缺氧和外源H2S的反应依赖于内皮、NO、cGMP、K+通道和Cl-/HCO3-交换。冠状动脉中H2S的产生可被CBS抑制（AOAA）阻断，但不能被CSE抑制（PPG）阻断。这些数据表明H2S是冠状动脉缺氧反应的内源性介质。在三种产生H2S的酶中，在血管平滑肌中表达的CBS似乎是冠状动脉缺氧松弛过程中产生H2S的最重要酶。只有当CBS活性受到抑制时，其他产生h2s的酶的作用才会变得明显。
Hypoxia-induced coronary artery vasodilatation protects the heart by increasing blood flow under ischemic conditions, however its mechanism is not fully elucidated. Hydrogen sulfide (H2S) is reported to be an oxygen sensor/transducer in the vasculature. The present study aimed to identify and characterise the role of H2S in the hypoxic response of the coronary artery, and to define the H2S synthetic enzymes involved. Immunoblotting and immunohistochemistry showed expression of all three H2S-producing enzymes, cystathionine-beta-synthase (CBS), cystathionine-y-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST), in porcine coronary artery. Artery segments were mounted for isometric tension recording; hypoxia caused a transient endothelium-dependent contraction followed by prolonged endothelium -independent relaxation. The CBS inhibitor aminooxyacetate (AOAA) reduced both phases of the hypoxic response. The CSE inhibitor DL-propargylglycine (PPG) and aspartate (limits MPST) had no effect alone, but when applied together with AOAA the hypoxic relaxation response was further reduced. Exogenous H2S (Na2S and NaHS) produced concentration -dependent contraction followed by prolonged relaxation. Responses to both hypoxia and exogenous H2S were dependent on the endothelium, NO, cGMP, K+ channels and Cl-/HCO3- exchange. H2S production in coronary arteries was blocked by CBS inhibition (AOAA), but not by CSE inhibition (PPG). These data show that H2S is an endogenous mediator of the hypoxic response in coronary arteries. Of the three H2S-producing enzymes, CBS, expressed in the vascular smooth muscle, appears to be the most important for H2S generated during hypoxic relaxation of the coronary artery. A contribution from other H2S-producing enzymes only becomes apparent when CBS activity is inhibited.