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

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.

Immuno-inflammatory pathogenesis in ischemic heart disease: perception and knowledge for neutrophil recruitment

“…Adipose tissue lipolysis and cardiomyocyte lipid accumulation augmented cardiac inflammation. Inhibition of adipose tissue lipolysis reduces lipid droplet accumulation, attenuates neutrophil infiltration, and improves cardiac function ( 60 ). Exocytosis is also a factor affecting NR.…”

Involvement of protein kinases associated signal transduction mechanisms in cardiac diseases

“…In fact, p38 MAPK has been demonstrated to serve as a mediator of ischemic preconditioning [85]. However, during myocardial infarction and angina, activation of MAPK signaling leads to increased cardiac damage and dysfunction, while specific activation of the p38 MAPK pathway has been implicated in the development of myocardial hypertrophy and fibrosis, which result in heart failure [86]. Recently, p38 MAPK has been shown to suppress neutrophil-heart-adipose tissue crosstalk and act as a switch in cardiac adaptation to cardiac dysfunction during the development of heart failure [87].…”

Cardiac ischemia modulates white adipose tissue in a depot-specific manner

“…It catalyzes the hydrolysis from TAGs to DAGs and free fatty acids. Adipocyte ATGL is a major player of whole-body lipid metabolism and glucose homeostasis ( Schreiber et al, 2019 ) and has been shown to be involved in cardiac pathologies as pressure overload ( Parajuli et al, 2018 ; Salatzki et al, 2018 ; Bottermann et al, 2022 ), catecholamine-induced heart failure ( Takahara et al, 2021 ; Thiele et al, 2021 ) or myocardial infarction ( Bottermann et al, 2020 ).…”