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We reported the emergence of Orai3 activity during EACH. This study aimed to characterize how inflammation regulates store-independent activation of Orai3-calcium influx and to evaluate the functional role of this influx. Isoproterenol infusion or abdominal aortic banding triggered EACH. TNF\u03b1 or conditioned medium from cardiac CD11b\/c cells activated either <jats:italic>in vivo<\/jats:italic> [isolated from rats displaying EACH], or <jats:italic>in vitro<\/jats:italic> [isolated from normal rats and activated with lipopolysaccharide], were added to adult cardiomyocytes before measuring calcium entry, cell hypertrophy and cell injury. Using intramyocardial injection of siRNA, Orai3 was <jats:italic>in vivo<\/jats:italic> knockdown during EACH to evaluate its protective activity in heart failure. Inflammatory CD11b\/c cells trigger a store-independent calcium influx in hypertrophied cardiomyocytes, that is mimicked by TNF\u03b1. Pharmacological or molecular (siRNA) approaches demonstrate that this calcium influx, depends on TNFR<jats:sub>2<\/jats:sub>, is Orai3-driven, and elicits cardiomyocyte hypertrophy and resistance to oxidative stress. Neutralization of Orai3 inhibits protective GSK3\u03b2 phosphorylation, impairs EACH and accelerates heart failure. Orai3 exerts a pathophysiological protective impact in EACH promoting hypertrophy and resistance to oxidative stress. We highlight inflammation arising from CD11b\/c cells as a potential trigger of TNFR<jats:sub>2<\/jats:sub>- and Orai3-dependent signaling pathways.<\/jats:p>","DOI":"10.1038\/s41598-019-42452-y","type":"journal-article","created":{"date-parts":[[2019,4,15]],"date-time":"2019-04-15T10:02:52Z","timestamp":1555322572000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cardiac inflammatory CD11b\/c cells exert a protective role in hypertrophied cardiomyocyte by promoting TNFR2- and Orai3- dependent signaling"],"prefix":"10.1038","volume":"9","author":[{"given":"Mathilde","family":"Keck","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathilde","family":"Flamant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Mougenot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Favier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrice","family":"Atassi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Barbier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1452-6009","authenticated-orcid":false,"given":"Sophie","family":"Nadaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Marie","family":"Lompr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-S\u00e9bastien","family":"Hulot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0598-5545","authenticated-orcid":false,"given":"Catherine","family":"Pavoine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,4,15]]},"reference":[{"key":"42452_CR1","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1007\/s004240050739","volume":"437","author":"M van Bilsen","year":"1998","unstructured":"van Bilsen, M., van der Vusse, G. 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