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Cardiomyocyte p38 MAPKα suppresses a heart-adipose tissue-neutrophil crosstalk in heart failure development
Katharina Bottermann1,2, Lisa Kalfhues1, Rianne Nederlof1
1Institute of Cardiovascular Physiology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University Düsseldorf, Postfach 101007, 40001, Düsseldorf, Germany.
Insights
p38 MAP Kinase α (p38 MAPKα) deficiency in cardiomyocytes exacerbates cardiac hypertrophy by causing metabolic dysfunction and inflammation. Targeting adipose tissue lipolysis and neutrophils improves cardiac function, revealing a novel therapeutic pathway.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cardiac Metabolism
Background:
- The role of p38 MAP Kinase α (p38 MAPKα) in pathological cardiac hypertrophy remains unclear.
- Cardiac stress response involves p38 MAPKα, but its specific function in maladaptive hypertrophy needs definition.
Purpose of the Study:
- To investigate the function of cardiomyocyte-specific p38 MAPKα in angiotensin II-induced cardiac hypertrophy.
- To elucidate the mechanisms underlying cardiac dysfunction, metabolic changes, and inflammation in the absence of p38 MAPKα.
Main Methods:
- Utilized tamoxifen-inducible cardiomyocyte-specific p38 MAPKα knockout (iCMp38αKO) mice.
- Administered angiotensin II (AngII) to induce cardiac hypertrophy and pressure overload.
- Assessed cardiac function via echocardiography, transcriptomics, histology, and immune cell analysis.
- Investigated the effects of inhibiting adipose tissue lipolysis (Atglistatin) and targeting neutrophils (anti-Ly6G antibody).
Main Results:
- AngII infusion in iCMp38αKO mice led to rapid left ventricular (LV) dilatation and ectopic lipid deposition in cardiomyocytes.
- Observed downregulation of oxidative phosphorylation, TCA cycle, and fatty acid metabolism transcripts.
- Significant enhancement of cardiac inflammation involving neutrophils, macrophages, B-cells, and T-cells.
- Inhibition of adipose tissue lipolysis reduced cardiac lipid accumulation and neutrophil infiltration, improving cardiac function.
- Targeting neutrophils reduced LV dilation and improved systolic function in iCMp38αKO mice.
Conclusions:
- p38 MAPKα is essential for cardiac adaptation to pressure overload, mitigating metabolic dysfunction and inflammation.
- Adipose tissue lipolysis and cardiomyocyte lipid accumulation exacerbate cardiac inflammation and LV dilatation.
- Neutrophils play a critical role in rapid left ventricular dilatation during maladaptive hypertrophy.
- A novel heart-adipose tissue-immune cell crosstalk is identified as a potential therapeutic target in cardiac pathologies.
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.
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