title: Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor-mediated vasorelaxation in transgenic cystathionine beta synthase-deficient mice.
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 μM). 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.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Zhongjian
authors.initials: Z
authors.lastname: Cheng
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jiang
authors.forename: Warren D
authors.initials: WD
authors.lastname: Kruger
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
authors.forename: Sapna
authors.initials: S
authors.lastname: Gupta
authors.forename: Karthik
authors.initials: K
authors.lastname: Mallilankaraman
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Schafer
authors.forename: William
authors.initials: W
authors.lastname: Durante
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Yang
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000209:etiology; D002460:Cell Line; D003541:Cystathionine beta-Synthase / Q000235:genetics*; D017353:Gene Deletion; D006710:Homocysteine / Q000097:blood; D006801:Humans; D020138:Hyperhomocysteinemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008638:Mesenteric Arteries / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009589:Nitrogen Oxides / Q000378:metabolism; D014664:Vasodilation
chemical_list: D001685:Biological Factors; D009589:Nitrogen Oxides; C067410:endothelium-dependent hyperpolarization factor; D006710:Homocysteine; D003541:Cystathionine beta-Synthase