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TGR5 is shown to express in hearts, but its functional role in diabetes-induced cardiac hypertrophy remained unclear. The current study investigated the role of TGR5 on high glucose-induced hypertrophy of H9C2 cells. After incubation with a high level of glucose, H9C2 cells showed hypertrophic responses. Activation of TGR5 by lithocholic acid (LCA) ameliorated cell hypertrophy and enhanced SERCA2a and phosphorylated phospholamban (PLN) expression in H9C2 cells. Triamterene inhibited these effects at an effective dose to block TGR5. However, LCA failed to modify the free radical elevation induced by high-glucose in the H9c2 cells. Moreover, PKA inhibitors, but not an Epac blocker, markedly improved hyperglycemia-induced hypertrophy and attenuated the increased SERCA2a expression by LCA; it also attenuated the phosphorylated PLN and SERCA2a protein expression levels in high glucose-treated H9C2 cells. In conclusion, TGR5 activation stimulated protein kinase A (PKA) to enhance PLN phosphorylation, which activated SERCA2a to remove Ca<jats:sup>2+<\/jats:sup> from cytosol to sarcoplasmic reticulum in addition to the reduction of calcineurin\/NFAT pathway signaling to ameliorate the hyperglycemia-induced cardiac hypertrophy shown in cardiomyocytes. TGR5 may service as a new target in the control of diabetic cardiomyopathy.<\/jats:p>","DOI":"10.1038\/s41598-019-40002-0","type":"journal-article","created":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T11:07:05Z","timestamp":1551870425000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["TGR5 activation ameliorates hyperglycemia-induced cardiac hypertrophy in H9c2 cells"],"prefix":"10.1038","volume":"9","author":[{"given":"Kai-Chun","family":"Cheng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei-Ting","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feng Yu","family":"Kuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhih-Cherng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingxiao","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4522-584X","authenticated-orcid":false,"given":"Juei-Tang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,3,6]]},"reference":[{"key":"40002_CR1","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1146\/annurev.biochem.72.121801.161712","volume":"72","author":"DW Russell","year":"2003","unstructured":"Russell, D. 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