FCCC LOGO Faculty Publications
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   
Back to previous list
Abstract
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)
Notes
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