The goal of this project is to address the role of a subset of histone deacetylase (HDAC) enzymes, class I HDACs, in the control of diastolic heart failure. Each year more than 600,000 cases of heart failure (HF) are diagnosed in the United States, adding to the more than 5 million adults with this condition;costs of care are estimated at $34.8 billion per year. About half of these patients have heart failure with preserved ejection fraction (HFpEF), or diastolic heart failure. Aging and hypertension are major risk factors for the development of HFpEF. Over the last two decades, systolic heart failure (sHF) patients have seen clinical benefits through pharmacological management;unfortunately, standard-of-care sHF medications have failed to show efficacy in large clinical trials in patients with HFpEF. Histone deacetylases (HDACs) catalyze removal of acetyl groups from lysine residues in a variety of proteins. The 18 mammalian HDACs are encoded by distinct genes and fall into four classes (I, II, III and IV). Broad-spectrum, 'pan'inhibitors of HDAC catalytic activity are marketd for cancer. Our preliminary data demonstrate that pan-HDAC inhibition is profoundly protective in a rodent model of HFpEF induced by chronic hypertension. HDAC inhibition blocked cardiac hypertrophy and fibrosis, improved diastolic cardiac function, and prolonged lifespan even in the face of sustained hypertension. In subsequent studies we determined that class I HDAC- selective inhibition blocks cardiac fibrosis through a mechanism associated with induction of anti-inflammatory regulatory T cells (Tregs). These results suggest an unanticipated application for isoform-selective HDAC inhibitors for the treatment of human HFpEF. This proposal is designed to address the overall hypothesis that class I HDACs promote diastolic dysfunction in the aging heart by triggering ventricular inflammation and fibrosis. Results from these studies should provide novel insights into the molecular basis of diastolic heart failure, and could form the foundation for innovative approaches to drug discovery for HFpEF based on isoform- selective HDAC inhibition.
Heart failure is a major health problem and growing economic burden worldwide. With greater than five million heart failure patients in the U.S. alone, treatment of this condition represents an estimated annual cost to the American health care system of over $37 billion. The research outlined in this proposal should provide a foundation for discovery of novel therapeutics to treat patient suffering from age-related cardiac dysfunction.
|Jeong, Mark Y; Lin, Ying H; Wennersten, Sara A et al. (2018) Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism. Sci Transl Med 10:|
|Angiolilli, Chiara; Kabala, Pawel A; Grabiec, Aleksander M et al. (2017) Histone deacetylase 3 regulates the inflammatory gene expression programme of rheumatoid arthritis fibroblast-like synoviocytes. Ann Rheum Dis 76:277-285|
|Stratton, Matthew S; Koch, Keith A; McKinsey, Timothy A (2017) p38?: A Profibrotic Signaling Nexus. Circulation 136:562-565|
|Hooker, Jacob M; Strebl, Martin G; Schroeder, Frederick A et al. (2017) Imaging cardiac SCN5A using the novel F-18 radiotracer radiocaine. Sci Rep 7:42136|
|Schuetze, Katherine B; Stratton, Matthew S; Blakeslee, Weston W et al. (2017) Overlapping and Divergent Actions of Structurally Distinct Histone Deacetylase Inhibitors in Cardiac Fibroblasts. J Pharmacol Exp Ther 361:140-150|
|Blakeslee, Weston W; Lin, Ying-Hsi; Stratton, Matthew S et al. (2017) Class I HDACs control a JIP1-dependent pathway for kinesin-microtubule binding in cardiomyocytes. J Mol Cell Cardiol 112:74-82|
|Aiello, Robert J; Bourassa, Patricia-Ann; Zhang, Qing et al. (2017) Tryptophan hydroxylase 1 Inhibition Impacts Pulmonary Vascular Remodeling in Two Rat Models of Pulmonary Hypertension. J Pharmacol Exp Ther 360:267-279|
|Zeng, Qingchun; Song, Rui; Fullerton, David A et al. (2017) Interleukin-37 suppresses the osteogenic responses of human aortic valve interstitial cells in vitro and alleviates valve lesions in mice. Proc Natl Acad Sci U S A 114:1631-1636|
|Blakeslee, Weston W; Demos-Davies, Kimberly M; Lemon, Douglas D et al. (2017) Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy. Pediatr Res 82:642-649|
|Habibian, Justine S; Jefic, Mitra; Bagchi, Rushita A et al. (2017) DUSP5 functions as a feedback regulator of TNF?-induced ERK1/2 dephosphorylation and inflammatory gene expression in adipocytes. Sci Rep 7:12879|
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