Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor-mediated vasorelaxation in transgenic cystathionine beta synthase-deficient mice
Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor-mediated vasorelaxation in transgenic cystathionine beta synthase-deficient mice
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DOI：
10.1182/blood-2011-01-333310
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发表时间：
2011-08-18
期刊：
影响因子：
20.3
通讯作者：
Wang, Hong
中科院分区：
文献类型：
--
作者：
Cheng, Zhongjian;Jiang, Xiaohua;Wang, Hong
高同型半胱氨酸血症（HHcy）与内皮功能障碍（艾德）有关，但其机制尚不清楚。在这项研究中，我们研究了在我们新建立的严重HHcy小鼠模型（血浆总同型半胱氨酸，169.5 μ M）中，HHcy诱导的微血管艾德的作用和机制。我们发现，严重的高同型半胱氨酸损害一氧化氮（NO）和内皮源性超极化因子（EDHF）介导的，内皮依赖性舒张小肠系膜动脉（SMA）。非内皮依赖性和前列环素介导的内皮依赖性舒张作用没有改变。非选择性钙激活钾通道（K-Ca）抑制剂完全阻断EDHF介导的舒张。小电导K-Ca（SK）或中电导K-Ca（IK）的选择性阻断剂未能抑制HHcy小鼠EDHF介导的舒张。HHcy可增加平滑肌细胞SK 3和IK 1蛋白、超氧阴离子（O-2（-））和3-硝基酪氨酸的含量。用抗氧化剂和过氧亚硝酸盐（ONOO-）抑制剂预孵育改善了内皮依赖性和EDHF介导的舒张作用，并降低了HHcy小鼠SMA中O-2（-）的产生。此外，EDHF介导的舒张抑制ONOO-和防止过氧化氢酶在对照组小鼠。最后，L-同型半胱氨酸刺激O-2（-）的生产，这是逆转的抗氧化剂，并增加SK/IK蛋白水平和酪氨酸硝化在培养的人心脏微血管内皮细胞。我们的研究结果表明，HHCy通过氧化和酪氨酸硝化相关机制抑制SK/IK活性，从而损害SMAs的EDHF松弛。（血。2011;118（7）：1998-2006）
Hyperhomocysteinemia (HHcy) is associated with endothelial dysfunction (ED), but the mechanism is largely unknown. In this study, we investigated the role and mechanism of HHcy-induced ED in microvasculature in our newly established mouse model of severe HHcy (plasma total homocysteine, 169.5 mu M). We found that severe HHcy impaired nitric oxide (NO)- and endothelium-derived hyperpolarizing factor (EDHF)-mediated, endothelium-dependent relaxations of small mesenteric arteries (SMAs). Endothelium-independent and prostacyclin-mediated endothelium-dependent relaxations were not changed. A nonselective Ca2+-activated potassium channel (K-Ca) inhibitor completely blocked EDHF-mediated relaxation. Selective blockers for small-conductance K-Ca (SK) or intermediate-conductance K-Ca (IK) failed to inhibit EDHF-mediated relaxation in HHcy mice. HHcy increased the levels of SK3 and IK1 protein, superoxide (O-2(-)), and 3-nitrotyrosine in the endothelium of SMAs. Preincubation with antioxidants and peroxynitrite (ONOO-) inhibitors improved endothelium-dependent and EDHF-mediated relaxations and decreased O-2(-) production in SMAs from HHcy mice. Further, EDHF-mediated relaxation was inhibited by ONOO- and prevented by catalase in the control mice. Finally, L-homocysteine stimulated O-2(-) production, which was reversed by antioxidants, and increased SK/IK protein levels and tyrosine nitration in cultured human cardiac microvascular endothelial cells. Our results suggest that HHcy impairs EDHF relaxation in SMAs by inhibiting SK/IK activities via oxidation-and tyrosine nitration-related mechanisms. (Blood. 2011;118(7):1998-2006)