Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor-mediated vasorelaxation in transgenic cystathionine beta synthase-deficient Mice

Zhongjian Cheng, Xiaohua Jiang, Warren D. Kruger, Domenico Praticò, Sapna Gupta, Karthik Mallilankaraman, Muniswamy Madesh, Andrew I. Schafer, William Durante, Xiaofeng Yang, Hong Wang

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

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, 169.5μM). 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 (KCa) inhibitor completely blocked EDHF-mediated relaxation. Selective blockers for small-conductance KCa (SK) or intermediate-conductance KCa (IK) failed to inhibit EDHF-mediated relaxation in HHcy mice. HHcy increased the levels of SK3 and IK1 protein, superoxide (O2-), and 3-nitrotyrosine in the endothelium of SMAs. Preincubation with antioxidants and peroxynitrite (ONOO-) inhibitors improved endothelium-dependent and EDHF-mediated relaxations and decreased O2- 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 O2- 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.

Original languageEnglish (US)
Pages (from-to)1998-2006
Number of pages9
JournalBlood
Volume118
Issue number7
DOIs
StatePublished - Aug 18 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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