Abstract 671 p38 MAPKα is a key regulator of cardiac glucose metabolism for adapting to pressure overload

Introduction: The heart utilizes different substrates to maintain a high rate of ATP production to ensure a sufficient cardiac performance, even when nutrient supply is altered. Throughout the progression of heart failure (HF), the ability for the heart to switch substrates may be impaired even before overt cardiac dysfunction. This loss of metabolic flexibility and insulin sensitivity may promote HF. To elucidate the underlying mechanisms of metabolic remodeling contributing to the establishment of HF, we investigated the influence of p38 MAPKα signaling on cardiac metabolism during the early phase of HF development.

Methods and Results: We use a mouse model with a cardiomyocyte specific, tamoxifen inducible p38 MAPKα deletion (iCMp38α KO). To induce pressure overload, we expose these mice to angiotensin II (AngII) by implanting osmotic mini pumps (1.5 mg/kg/d). Only 48h after the onset of AngII treatment echocardiography revealed a massive left ventricular dilation and an impaired cardiac function in iCMp38 KO hearts (ejection fraction [%]: KO 29±7.6, Ctrl 49±12). Substrate utilization measured by NMR spectroscopy with ¹³C-labeled substrates showed that iCMp38α KO hearts failed to upregulate glucose utilization after insulin stimulation already under baseline conditions. This cardiac insulin resistance in iCMp38α KO hearts was associated with a decreased GLUT4 protein amount (app. 50%) and a reduced plasma membrane translocation after insulin stimulation (app. 75%), without compromising phoyphorylation levels of proteins mediating intracellular insulin signaling transduction (incl. AKT isoforms, AS160, PRAS 40, and GSK3β). Surprisingly, AngII treatment also led to increased plasma insulin levels in iCMp38α KO hearts suggesting a crosstalk between the stressed heart and pancreatic β cells. However, pancreatic islets did not reveal differentially expressed insulin transcripts, pointing to a potential influence on insulin processing or secretion.

In cardiomyocytes, increased plasma insulin levels in iCMp38α KO mice enhanced cardiac AKT^S473 phosphorylation. Activation of AKT in turn reduced activating AMPKT¹⁷², and increased inhibitory AMPK^S485 phosphorylation, shifting AMPK to the inactive form which might contribute to a reduced energy supply in pressure overloaded KO hearts. This insulin mediated AMPK inhibition was not found in cardiomyocyte specific AKT KO hearts, underlining the importance of AKT in AMPK inhibition.

Conclusion: iCMp38α KO mice develop hyperinsulinemia, cardiac insulin resistance, and an extensive metabolic depression, contributing to the progression of HF. Thus, p38 MAPKα signaling is a key regulator in the adaption of cardiac glucose metabolism due to elevated workload and potentially in the interorgan communication between the failing heart and pancreatic tissue.


p38 MAPKα is a key regulator of cardiac glucose metabolism for adapting to pressure overload
L. Kalfhues¹, K. Bottermann², V. Oenarto¹, C. Galang¹, L. Leitner¹, U. Flögel³, V. Raje⁴, T. Harris⁴, A. Gödecke¹
¹Institut für Herz- und Kreislaufphysiologie, Universitätsklinikum Düsseldorf, Düsseldorf; ²Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf; ³Institut für Molekulare Kardiologie, Universitätsklinikum Düsseldorf, Düsseldorf; ⁴Department of Pharmacology, University of Virginia, Charlottesville, VA, US;
Introduction: The heart utilizes different substrates to maintain a high rate of ATP production to ensure a sufficient cardiac performance, even when nutrient supply is altered. Throughout the progression of heart failure (HF), the ability for the heart to switch substrates may be impaired even before overt cardiac dysfunction. This loss of metabolic flexibility and insulin sensitivity may promote HF. To elucidate the underlying mechanisms of metabolic remodeling contributing to the establishment of HF, we investigated the influence of p38 MAPKα signaling on cardiac metabolism during the early phase of HF development. Methods and Results: We use a mouse model with a cardiomyocyte specific, tamoxifen inducible p38 MAPKα deletion (iCMp38α KO). To induce pressure overload, we expose these mice to angiotensin II (AngII) by implanting osmotic mini pumps (1.5 mg/kg/d). Only 48h after the onset of AngII treatment echocardiography revealed a massive left ventricular dilation and an impaired cardiac function in iCMp38 KO hearts (ejection fraction [%]: KO 29±7.6, Ctrl 49±12). Substrate utilization measured by NMR spectroscopy with ¹³C-labeled substrates showed that iCMp38α KO hearts failed to upregulate glucose utilization after insulin stimulation already under baseline conditions. This cardiac insulin resistance in iCMp38α KO hearts was associated with a decreased GLUT4 protein amount (app. 50%) and a reduced plasma membrane translocation after insulin stimulation (app. 75%), without compromising phoyphorylation levels of proteins mediating intracellular insulin signaling transduction (incl. AKT isoforms, AS160, PRAS 40, and GSK3β). Surprisingly, AngII treatment also led to increased plasma insulin levels in iCMp38α KO hearts suggesting a crosstalk between the stressed heart and pancreatic β cells. However, pancreatic islets did not reveal differentially expressed insulin transcripts, pointing to a potential influence on insulin processing or secretion. In cardiomyocytes, increased plasma insulin levels in iCMp38α KO mice enhanced cardiac AKT^S473 phosphorylation. Activation of AKT in turn reduced activating AMPKT¹⁷², and increased inhibitory AMPK^S485 phosphorylation, shifting AMPK to the inactive form which might contribute to a reduced energy supply in pressure overloaded KO hearts. This insulin mediated AMPK inhibition was not found in cardiomyocyte specific AKT KO hearts, underlining the importance of AKT in AMPK inhibition. Conclusion: iCMp38α KO mice develop hyperinsulinemia, cardiac insulin resistance, and an extensive metabolic depression, contributing to the progression of HF. Thus, p38 MAPKα signaling is a key regulator in the adaption of cardiac glucose metabolism due to elevated workload and potentially in the interorgan communication between the failing heart and pancreatic tissue.
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