Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis
Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis
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DOI：
10.1161/circulationaha.113.002208
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发表时间：
2013-06-25
期刊：
影响因子：
37.8
通讯作者：
Wang, Rui
中科院分区：
文献类型：
--
作者：
Mani, Sarathi;Li, Hongzhu;Wang, Rui
研究背景胱硫醚裂解酶(CSE)在心血管系统中产生硫化氢(H_2S)。小鼠体内CSE缺乏导致内源性硫化氢水平降低，血压随年龄增加，内皮依赖性血管松弛功能受损。方法和结果6周龄CSE基因敲除小鼠和野生型小鼠分别饲喂对照饲料或致动脉粥样硬化白瓜型饲料12周。然后分析血脂和同型半胱氨酸水平、血压、氧化应激、主动脉根部动脉粥样硬化病变大小、细胞增殖和黏附分子表达。以致动脉粥样硬化饮食喂养的CSE基因敲除小鼠在主动脉根部出现早期脂肪条纹病变，血浆胆固醇和低密度脂蛋白胆固醇水平升高，高同型半胱氨酸血症，皮损氧化应激和黏附分子表达增加，并促进主动脉内膜增殖。用NaHS治疗CSE基因敲除小鼠，而不是N-乙酰半胱氨酸或依折麦布，可以抑制动脉粥样硬化的加速发展。CSE和载脂蛋白E双基因敲除小鼠较单纯载脂蛋白E或CSE基因敲除小鼠更易加重动脉粥样硬化的发生。结论内源性合成的硫化氢通过减少血管内膜增殖和抑制黏附分子的表达，保护血管组织免受动脉粥样硬化的损伤。内源性硫化氢生成减少使动物易于血管重塑和动脉粥样硬化的早期发展。CSE/H_2S通路是防治动脉粥样硬化的重要治疗靶点。
BackgroundCystathionine -lyase (CSE) produces hydrogen sulfide (H2S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H2S level, an age-dependent increase in blood pressure, and impaired endothelium-dependent vasorelaxation. To date, there is no direct evidence for a causative role of altered metabolism of endogenous H2S in atherosclerosis development.Methods and ResultsSix-week-old CSE gene knockout and wild-type mice were fed with either a control chow or atherogenic paigen-type diet for 12 weeks. Plasma lipid profile and homocysteine levels, blood pressure, oxidative stress, atherosclerotic lesion size in the aortic roots, cell proliferation, and adhesion molecule expression were then analyzed. CSE-knockout mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, elevated plasma levels of cholesterol and low-density lipoprotein cholesterol, hyperhomocysteinemia, increased lesional oxidative stress and adhesion molecule expression, and enhanced aortic intimal proliferation. Treatment of CSE-knockout mice with NaHS, but not N-acetylcysteine or ezetimibe, inhibited the accelerated atherosclerosis development. Double knockout of CSE and apolipoprotein E gene expression in mice exacerbated atherosclerosis development more than that in the mice with only apolipoprotein E or CSE knockout.ConclusionsEndogenously synthesized H2S protects vascular tissues from atherogenic damage by reducing vessel intimal proliferation and inhibiting adhesion molecule expression. Decreased endogenous H2S production predisposes the animals to vascular remodeling and early development of atherosclerosis. The CSE/H2S pathway is an important therapeutic target for protection against atherosclerosis.