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Hydrogen sulfide (H<jats:sub>2<\/jats:sub>S) has potent anti\u2010inflammatory, anti\u2010oxidative, and anti\u2010apoptotic effects. Therefore, in the present study we examined whether H<jats:sub>2<\/jats:sub>S ameliorates Hcy\u2010induced mitochondrial toxicity which led to endothelial dysfunction in part, by epigenetic alterations in mouse brain endothelial cells (bEnd3). The bEnd3 cells were exposed to 100\u2009\u03bcM Hcy treatment in the presence or absence of 30\u2009\u03bcM NaHS (donor of H<jats:sub>2<\/jats:sub>S) for 24\u2009h. Hcy\u2010activate NMDA receptor and induced mitochondrial toxicity by increased levels of Ca<jats:sup>2+<\/jats:sup>, NADPH\u2010oxidase\u20104 (NOX\u20104) expression, mitochondrial dehydrogenase activity and decreased the level of nitrate, superoxide dismutase (SOD\u20102) expression, mitochondria membrane potentials, ATP production. To confirm the role of epigenetic, 5\u2032\u2010azacitidine (an epigenetic modulator) treatment was given to the cells. Pretreatment with NaHS (30\u2009\u03bcM) attenuated the Hcy\u2010induced increased expression of DNMT1, DNMT3a, Ca<jats:sup>2+<\/jats:sup>, and decreased expression of DNMT3b in bEND3 cells. Furthermore, NaHS treatment also mitigated mitochondrial oxidative stress (NOX4, ROS, and NO) and restored ATP that indicates its protective effects against mitochondrial toxicity. Additional, NaHS significantly alleviated Hcy\u2010induced LC3\u2010I\/II, CSE, Atg3\/7, and low p62 expression which confirm its effect on mitophagy. Likewise, NaHS also restored level of eNOS, CD31, VE\u2010cadherin and ET\u20101 and maintains endothelial function in Hcy treated cells. Molecular inhibition of NMDA receptor by using small interfering RNA showed protective effect whereas inhibition of H<jats:sub>2<\/jats:sub>S production by propargylglycine (PG) (inhibitor of enzyme CSE) showed mitotoxic effect. Taken together, results demonstrate that, administration of H<jats:sub>2<\/jats:sub>S protected the cells from HHcy\u2010induced mitochondrial toxicity and endothelial dysfunction. J. Cell. Physiol. 230: 378\u2013394, 2015. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.24722","type":"journal-article","created":{"date-parts":[[2014,7,24]],"date-time":"2014-07-24T04:52:55Z","timestamp":1406177575000},"page":"378-394","source":"Crossref","is-referenced-by-count":82,"title":["Hydrogen Sulfide Epigenetically Attenuates Homocysteine\u2010Induced Mitochondrial Toxicity Mediated Through NMDA Receptor in Mouse Brain Endothelial (bEnd3) Cells"],"prefix":"10.1002","volume":"230","author":[{"given":"Pradip K.","family":"Kamat","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics School of Medicine University of Louisville Louisville Kentucky"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anuradha","family":"Kalani","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics School of Medicine University of Louisville Louisville 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