Cardiomyocyte p38 MAPKα suppresses a heart-adipose tissue-neutrophil crosstalk in heart failure development

Basic Res Cardiol. 2022 Oct 7;117(1):48. doi: 10.1007/s00395-022-00955-2.

Abstract

Although p38 MAP Kinase α (p38 MAPKα) 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 MAPKα KO mice (iCMp38αKO) and assessed cardiac function by echocardiography, complemented by transcriptomic, histological, and immune cell analysis. AngII treatment after inactivation of p38 MAPKα in CM results in left ventricular (LV) dilatation within 48 h (EDV: BL: 83.8 ± 22.5 µl, 48 h AngII: 109.7 ± 14.6 µl) 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 iCMp38αKO mice and an improved systolic function (EF: 39.27 ± 14%). Thus, adipose tissue lipolysis and CM lipid accumulation augmented cardiac inflammation in iCMp38αKO mice. Neutrophils, in particular, triggered the rapid left ventricular dilatation. We provide the first evidence that p38 MAPKα 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.

Keywords: Cardiac inflammation; Lipolysis; Metabolic dysfunction; Pressure overload; p38 MAPKα.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism
  • Angiotensin II / metabolism
  • Animals
  • Cardiomegaly / metabolism
  • Fatty Acids / metabolism
  • Heart Failure*
  • Inflammation / metabolism
  • Lipase / metabolism
  • Lipase / therapeutic use
  • Lipids / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac* / metabolism
  • Neutrophils / metabolism
  • Tamoxifen / metabolism
  • Tamoxifen / therapeutic use
  • p38 Mitogen-Activated Protein Kinases / metabolism
  • p38 Mitogen-Activated Protein Kinases / therapeutic use

Substances

  • Fatty Acids
  • Lipids
  • Tamoxifen
  • Angiotensin II
  • p38 Mitogen-Activated Protein Kinases
  • Lipase