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However, effect of H<jats:sub>2<\/jats:sub>S or homocysteine on CBS and CSE expression, and cross-talk between CBS and CSE are unclear. We hypothesize that homocysteine and H<jats:sub>2<\/jats:sub>S regulate CBS and CSE expressions in a dose dependent manner in cardiomyocytes, and CBS deficiency induces cardiac CSE expression. To test the hypothesis, we treated murine atrial HL1 cardiomyocytes with increasing doses of homocysteine or Na<jats:sub>2<\/jats:sub>S\/GYY4137, a H<jats:sub>2<\/jats:sub>S donor, and measured the levels of CBS and CSE. We found that homocysteine upregulates CSE but downregulates CBS whereas Na<jats:sub>2<\/jats:sub>S\/GYY4137 downregulates CSE but upregulates CBS in a dose-dependent manner. Moreover, the Na<jats:sub>2<\/jats:sub>S-treatment downregulates specificity protein-1 (SP1), an inducer for CSE, and upregulates miR-133a that targets SP1 and inhibits cardiomyocytes hypertrophy. Conversely, in the homocysteine-treated cardiomyocytes, CBS and miR-133a were downregulated and hypertrophy was induced. <jats:italic>In vivo<\/jats:italic> studies using CBS+\/\u2212, a model for hyperhomocysteinemia, and sibling CBS+\/+ control mice revealed that deficiency of CBS upregulates cardiac CSE, plausibly by inducing SP1. In conclusion, we revealed a novel mechanism for H<jats:sub>2<\/jats:sub>S-mediated regulation of homocysteine metabolism in cardiomyocytes, and a negative feedback regulation between CBS and CSE in the heart.<\/jats:p>","DOI":"10.1038\/s41598-017-03776-9","type":"journal-article","created":{"date-parts":[[2017,6,9]],"date-time":"2017-06-09T15:53:34Z","timestamp":1497023614000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["H2S and homocysteine control a novel feedback regulation of cystathionine beta synthase and cystathionine gamma lyase in cardiomyocytes"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6422-2540","authenticated-orcid":false,"given":"Shyam Sundar","family":"Nandi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paras Kumar","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,16]]},"reference":[{"key":"3776_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/1475-2891-14-6","volume":"14","author":"P Ganguly","year":"2015","unstructured":"Ganguly, P. & Alam, S. F. Role of homocysteine in the development of cardiovascular disease. Nutr. J. \n                           14, 6, doi:10.1186\/1475-2891-14-6 (2015).","journal-title":"Nutr. J."},{"key":"3776_CR2","first-page":"405","volume":"17","author":"G Buccianti","year":"2004","unstructured":"Buccianti, G. et al. Plasma homocysteine levels and cardiovascular mortality in patients with end-stage renal disease. J. Nephrol \n                           17, 405\u2013410 (2004).","journal-title":"J. Nephrol"},{"key":"3776_CR3","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1056\/NEJM199707243370403","volume":"337","author":"O Nygard","year":"1997","unstructured":"Nygard, O. et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. N. Engl. J. Med. \n                           337, 230\u2013236, doi:10.1056\/NEJM199707243370403 (1997).","journal-title":"N. Engl. J. 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