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Cheng ZJ , Jiang XH , Kruger WD , Pratico D , Gupta S , Mallilankaraman K , Madesh M , Schafer AI , Durante W , Yang XF , Wang H
Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor-mediated vasorelaxation in transgenic cystathionine beta synthase-deficient mice
Blood. 2011 Aug;118(7) :1998-2006
PMID: WOS:000294011500040   
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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 Ca(2+)-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)
Cheng, Zhongjian Jiang, Xiaohua Kruger, Warren D. Pratico, Domenico Gupta, Sapna Mallilankaraman, Karthik Madesh, Muniswamy Schafer, Andrew I. Durante, William Yang, Xiaofeng Wang, Hong National Institutes of Health[HL67033, HL77288, HL82774, HL74966, HL94451, HL86699, SLORR27327, HL57299] This work was supported in part by National Institutes of Health grants HL67033, HL77288, and HL82774 (H.W.); HL74966 (W.D.); HL94451 (X.F.Y.); HL86699 and SLORR27327 (M.M); and HL57299 (W.D.K.). 38 Amer soc hematology Washington 808wc Rchgott rf, 1980, v288, p373