HDAC4-NCoR1/HDAC3 complex formation drives cardiometabolic disease

Harikrishnareddy Paluvai (Heidelberg)1, J. Huang (Heidelberg)1, S. Nazir (Heidelberg)1, J. Backs (Heidelberg)1

1Heidelberg University, Medical Faculty Heidelberg, Institute of Experimental Cardiology Department of Internal Medicine VIII, German Center for Cardiovascular Research (DZHK), Partner Site Heidelberg/Mannheim Heidelberg, Deutschland


Cardiometabolic diseases encompass a broad spectrum of conditions that link cardiovascular and metabolic disorders. Among these, one of the most challenging and increasingly prevalent conditions is Heart Failure with Preserved Ejection Fraction (HFpEF). Many individuals with HFpEF have metabolic syndrome due to the presence of conditions like hypertension, diabetes, and obesity. These risk factors contribute to the development and progression of HFpEF. New research suggest that histone deacetylases (HDACs) play a significant role in escalating HFpEF pathogenesis and enzymatic inhibition of HDACs by pan-HDAC inhibitors improvedcardiopulmonary structure and cardiac function in HFpEF rat and feline models. However, it remained unclear which of the different HDACs that are inhibited by SAHA is responsible for the improvement in HFpEF. Our unpublished clinical provide strong evidence that a class IIa HDAC, namely HDAC4, contributes to HFpEF pathogenesis. Cardiomyocyte-specific HDAC4 knockout mice (HDAC4-cKO) were protected from diastolic dysfunction upon high fat diet + L-NAME treatment (HFD+LNM). In vertebrates, class IIa HDACs were reported to be catalytically inactive epigenetic enzymes, and instead they form a class IIa corepressor complex in vivo with nuclear receptor corepressor 1 (NCoR1) and HDAC3 to repress HDAC4 targeted genes. Therefore, we hypothesized that disruption of the class IIa corepressor complex in vivo, could rescue diastolic dysfunction in a murine HFpEF model. We show that treatment with an allosteric HDAC4 inhibitor (RT2), that disrupts HDAC4 interaction with NCoR1/HDAC3 rescued diastolic dysfunction (E/E’: HFD+LNM+RT2, 26.32 ± 4.2, n=6 vs HFD+LNM +Veh 45.54 ±  4.46, n=6, p<0,0001) by disrupting HDAC4 binding to the class IIa corepressor complex.  Strikingly RT2, showed remarkable improvement of exercise capacity (meters: HFD+LNM+RT2, 327,0 ± 73.31, n=6 vs HFD+LNM+Veh 200 ± 43.88, n=6, p=0,0246) and reduced blood glucose levels (Blood glucose mg/dL: HFD+L-NAME+RT2 182.80 ± 14.06, n=5 vs HFD+L-NAME+Veh, 267.50 ± 56.82, n=6, p<0,0001 after 30 min in Glucose Tolerance Test) in HFpEF mice. Among the HFD+LNM+Vehand HFD+LNM+RT2 group, we see a significant decrease in body weight (body weight in gms HFD+LNM+RT2, 28 ± 1.5, n=6 vs HFD+LNM+Veh 33.6 ± 1.3, n=6, p <0,0001) suggesting that RT2 prevented diet induced weight gain in HFpEF mice. Mechanistically, we identified a cysteine residue required for NCoR1/HDAC3 binding that is sulfonated, thereby providing a potential mode of action of pathological HDAC4 activation. Overall, our in vivo findings emphasize a crucial role of HDAC4 in development of HFpEF and inhibition of HDAC4 by the allosteric inhibitor RT2 enhanced cardiac function and improved metabolic health in a murine HFpEF model. Our in vivo data suggests, that enzymatic HDAC4 activation causes diastolic dysfunction, obesity, and glucose intolerance in HFpEF pathogenesis. Therefore, inhibition of enzymatic HDAC4 activation by an allosteric inhibitor could be used as a potential therapeutic drug to treat HFpEF patients.

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