{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T16:40:55Z","timestamp":1790872855588,"version":"4.1.0"},"reference-count":38,"publisher":"American Society of Hematology","issue":"7","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,8,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u03bcM). We found that severe HHcy impaired nitric oxide (NO)\u2013 and endothelium-derived hyperpolarizing factor (EDHF)\u2013mediated, 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\u2212), and 3-nitrotyrosine in the endothelium of SMAs. Preincubation with antioxidants and peroxynitrite (ONOO\u2212) inhibitors improved endothelium-dependent and EDHF-mediated relaxations and decreased O2\u2212 production in SMAs from HHcy mice. Further, EDHF-mediated relaxation was inhibited by ONOO\u2212 and prevented by catalase in the control mice. Finally, L-homocysteine stimulated O2\u2212 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\u2013related mechanisms.<\/jats:p>","DOI":"10.1182\/blood-2011-01-333310","type":"journal-article","created":{"date-parts":[[2011,6,9]],"date-time":"2011-06-09T00:24:04Z","timestamp":1307579044000},"page":"1998-2006","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":59,"title":["Hyperhomocysteinemia impairs endothelium-derived hyperpolarizing factor\u2013mediated vasorelaxation in transgenic cystathionine beta synthase\u2013deficient mice"],"prefix":"10.1182","volume":"118","author":[{"given":"Zhongjian","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Pharmacology,"},{"name":"Cardiovascular Research Center, and"},{"name":"Thrombosis Research Center, Temple University School of Medicine, Philadelphia, 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