期刊
BASIC RESEARCH IN CARDIOLOGY
卷 117, 期 1, 页码 -出版社
SPRINGER HEIDELBERG
DOI: 10.1007/s00395-022-00955-2
关键词
p38 MAPK alpha; Pressure overload; Lipolysis; Metabolic dysfunction; Cardiac inflammation
资金
- Projekt DEAL
- German Research Foundation (DFG), Bonn, Germany [IRTG 1902]
- Dr. Sigrid Worch-Pohler-Stiftung, Dusseldorf, Germany
- National Institutes of Health [R01 DK101946]
The study found that p38 MAPK alpha plays a crucial role in alleviating metabolic dysfunction and inflammation during cardiac adaptation to pressure overload. Lipolysis in adipose tissue and lipid accumulation in cardiomyocytes exacerbate cardiac inflammation, with neutrophils particularly triggering rapid left ventricular dilation.
Although p38 MAP Kinase alpha (p38 MAPK alpha) 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 days via osmotic mini pumps in control and tamoxifen-inducible, cardiomyocyte (CM)-specific p38 MAPK alpha KO mice (iCMp38 alpha KO) and assessed cardiac function by echocardiography, complemented by transcriptomic, histological, and immune cell analysis. AngII treatment after inactivation of p38 MAPKa in CM results in left ventricular (LV) dilatation within 48 h (EDV: BL: 83.8 +/- 22.5 mu l, 48 h AngII: 109.7 +/- 14.6 mu l) 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 adipocytetriglyceride lipase (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 alpha KO mice and an improved systolic function (EF: 39.27 +/- 14%). Thus, adipose tissue lipolysis and CM lipid accumulation augmented cardiac inflammation in iCMp38 alpha KO mice. Neutrophils, in particular, triggered the rapid left ventricular dilatation. We provide the first evidence that p38 MAPK alpha acts as an essential switch in cardiac adaptation to PO by mitigating metabolic dysfunction and inflammation. Moreover, we identified a heart-adipose tissue-immune cell crosstalk, which might serve as new therapeutic target in cardiac pathologies.
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