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However, the joint effect of hyperhomocysteinemia (HHcy) and hyperglycemia (HG) on endothelial dysfunction (ED) and the underlying mechanisms have not been studied. Mild (22 \u00b5mol\/L) and moderate (88 \u00b5mol\/L) HHcy were induced in cystathionine \u03b2-synthase wild-type (Cbs+\/+) and heterozygous-deficient (Cbs\u2212\/+) mice by a high-methionine (HM) diet. HG was induced by consecutive injection of streptozotocin. We found that HG worsened HHcy and elevated Hcy levels to 53 and 173 \u00b5mol\/L in Cbs+\/+ and Cbs\u2212\/+ mice fed an HM diet, respectively. Both mild and moderate HHcy aggravated HG-impaired endothelium-dependent vascular relaxation to acetylcholine, which was completely abolished by endothelial nitric oxide synthase (eNOS) inhibitor NG-nitro-L-arginine methyl ester. HHcy potentiated HG-induced calpain activation in aortic endothelial cells isolated from Cbs mice. Calpain inhibitors rescued HHcy- and HHcy\/HG-induced ED in vivo and ex vivo. Moderate HHcy- and HG-induced \u03bc-calpain activation was potentiated by a combination of HHcy and HG in the mouse aorta. \u03bc-Calpain small interfering RNA (\u03bc-calpsiRNA) prevented HHcy\/HG-induced ED in the mouse aorta and calpain activation in human aortic endothelial cells (HAECs) treated with DL-Hcy (500 \u00b5mol\/L) and d-glucose (25 mmol) for 48 h. In addition, HHcy accelerated HG-induced superoxide production as determined by dihydroethidium and 3-nitrotyrosin staining and urinary 8-isoprostane\/creatinine assay. Antioxidants rescued HHcy\/HG-induced ED in mouse aortas and calpain activation in cultured HAECs. Finally, HHcy potentiated HG-suppressed nitric oxide production and eNOS activity in HAECs, which were prevented by calpain inhibitors or \u03bc-calpsiRNA. HHcy aggravated HG-increased phosphorylation of eNOS at threonine 497\/495 (eNOS-pThr497\/495) in the mouse aorta and HAECs. HHcy\/HG-induced eNOS-pThr497\/495 was reversed by \u00b5-calpsiRNA and adenoviral transduced dominant negative protein kinase C (PKC)\u03b22 in HAECs. HHcy and HG induced ED, which was potentiated by the combination of HHcy and HG via \u03bc-calpain\/PKC\u03b22 activation\u2013induced eNOS-pThr497\/495 and eNOS inactivation.<\/jats:p>","DOI":"10.2337\/db14-0784","type":"journal-article","created":{"date-parts":[[2014,10,29]],"date-time":"2014-10-29T02:33:21Z","timestamp":1414550001000},"page":"947-959","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":73,"title":["Hyperhomocysteinemia and Hyperglycemia Induce and Potentiate Endothelial Dysfunction via \u03bc-Calpain Activation"],"prefix":"10.2337","volume":"64","author":[{"given":"Zhongjian","family":"Cheng","sequence":"first","affiliation":[{"name":"1Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA"},{"name":"2Department of Pharmacology, Temple University School of Medicine, Philadelphia, 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PA"},{"name":"2Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jietang","family":"Mai","sequence":"additional","affiliation":[{"name":"1Center for Metabolic Disease Research, Temple University School of Medicine, Philadelphia, PA"},{"name":"2Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Mallilankaraman","sequence":"additional","affiliation":[{"name":"4Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh Kumar","family":"Gandhirajan","sequence":"additional","affiliation":[{"name":"4Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoru","family":"Eguchi","sequence":"additional","affiliation":[{"name":"3Center for Cardiovascular Research, Temple University School of Medicine, Philadelphia, PA"},{"name":"5Department of Physiology, Temple University School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Scalia","sequence":"additional","affiliation":[{"name":"3Center for Cardiovascular Research, Temple University School of Medicine, Philadelphia, PA"},{"name":"5Department of Physiology, Temple University School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muniswamy","family":"Madesh","sequence":"additional","affiliation":[{"name":"4Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA"},{"name":"6Department of Biochemistry, Temple University School of Medicine, Philadelphia, 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