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Anstalt \u00f6ffentlichen Rechts"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Basic Res Cardiol"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Although p38 MAP Kinase \u03b1 (p38 MAPK\u03b1) is generally accepted to play a central role in the cardiac stress response, to date its function in maladaptive cardiac hypertrophy is still not unambiguously defined. To induce a pathological type of cardiac hypertrophy we infused angiotensin II (AngII) for 2\u00a0days via osmotic mini pumps in control and tamoxifen-inducible, cardiomyocyte (CM)-specific p38 MAPK\u03b1 KO mice (iCMp38\u03b1KO) and assessed cardiac function by echocardiography, complemented by transcriptomic, histological, and immune cell analysis. AngII treatment after inactivation of p38 MAPK\u03b1 in CM results in left ventricular (LV) dilatation within 48\u00a0h (EDV: BL: 83.8\u2009\u00b1\u200922.5\u00a0\u00b5l, 48\u00a0h AngII: 109.7\u2009\u00b1\u200914.6\u00a0\u00b5l) and an ectopic lipid deposition in cardiomyocytes, reflecting a metabolic dysfunction in pressure overload (PO). This was accompanied by a concerted downregulation of transcripts for oxidative phosphorylation, TCA cycle, and fatty acid metabolism. Cardiac inflammation involving neutrophils, macrophages, B- and T-cells was significantly enhanced. Inhibition of adipose tissue lipolysis by the small molecule inhibitor of <jats:italic>adipocytetriglyceride lipase<\/jats:italic> (ATGL) Atglistatin reduced cardiac lipid accumulation by 70% and neutrophil infiltration by 30% and went along with an improved cardiac function. Direct targeting of neutrophils by means of anti Ly6G-antibody administration in vivo led to a reduced LV dilation in iCMp38\u03b1KO mice and an improved systolic function (EF: 39.27\u2009\u00b1\u200914%). Thus, adipose tissue lipolysis and CM lipid accumulation augmented cardiac inflammation in iCMp38\u03b1KO mice. Neutrophils, in particular, triggered the rapid left ventricular dilatation. We provide the first evidence that p38 MAPK\u03b1 acts as an essential switch in cardiac adaptation to PO by mitigating metabolic dysfunction and inflammation. Moreover, we identified a heart\u2013adipose tissue\u2013immune cell crosstalk, which might serve as new therapeutic target in cardiac pathologies.<\/jats:p>","DOI":"10.1007\/s00395-022-00955-2","type":"journal-article","created":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T13:04:18Z","timestamp":1665147858000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Cardiomyocyte p38 MAPK\u03b1 suppresses a heart\u2013adipose tissue\u2013neutrophil crosstalk in heart failure development"],"prefix":"10.1007","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4893-9298","authenticated-orcid":false,"given":"Katharina","family":"Bottermann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Kalfhues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4983-464X","authenticated-orcid":false,"given":"Rianne","family":"Nederlof","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Hemmers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia M.","family":"Leitner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vici","family":"Oenarto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Nemmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirjam","family":"Pfeffer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vidisha","family":"Raje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rene","family":"Deenen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8355-5524","authenticated-orcid":false,"given":"Patrick","family":"Petzsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heba","family":"Zabri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3644-2022","authenticated-orcid":false,"given":"Karl","family":"K\u00f6hrer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9340-3113","authenticated-orcid":false,"given":"Andreas S.","family":"Reichert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Grandoch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens W.","family":"Fischer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diran","family":"Herebian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Stegbauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1742-6043","authenticated-orcid":false,"given":"Thurl E.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9927-130X","authenticated-orcid":false,"given":"Axel","family":"G\u00f6decke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,7]]},"reference":[{"key":"955_CR1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1007\/s00395-019-0722-5","volume":"114","author":"L Bacmeister","year":"2019","unstructured":"Bacmeister L, Schwarzl M, Warnke S, Stoffers B, Blankenberg S, Westermann D, Lindner D (2019) Inflammation and fibrosis in murine models of heart failure. 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