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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG043822-02
Application #
8548228
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Kohanski, Ronald A
Project Start
2012-09-30
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$182,602
Indirect Cost
$64,477
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Stratton, Matthew S; Lin, Charles Y; Anand, Priti et al. (2016) Signal-Dependent Recruitment of BRD4 to Cardiomyocyte Super-Enhancers Is Suppressed by a MicroRNA. Cell Rep 16:1366-78
Angiolilli, Chiara; Grabiec, Aleksander M; Ferguson, Bradley S et al. (2016) Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression. Ann Rheum Dis 75:430-8
Stratton, Matthew S; McKinsey, Timothy A (2016) Epigenetic regulation of cardiac fibrosis. J Mol Cell Cardiol 92:206-13
Lin, Ying-Hsi; Warren, Chad M; Li, Jieli et al. (2016) Myofibril growth during cardiac hypertrophy is regulated through dual phosphorylation and acetylation of the actin capping protein CapZ. Cell Signal 28:1015-24
Reid, Brian G; Stratton, Matthew S; Bowers, Samantha et al. (2016) Discovery of novel small molecule inhibitors of cardiac hypertrophy using high throughput, high content imaging. J Mol Cell Cardiol 97:106-13
Zhao, Yuanbiao; Londono, Pilar; Cao, Yingqiong et al. (2015) High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat Commun 6:8243
Lemon, Douglas D; Harrison, Brooke C; Horn, Todd R et al. (2015) Promiscuous actions of small molecule inhibitors of the protein kinase D-class IIa HDAC axis in striated muscle. FEBS Lett 589:1080-8
Salian-Mehta, Smita; Xu, Mei; McKinsey, Timothy A et al. (2015) Novel Interaction of Class IIb Histone Deacetylase 6 (HDAC6) with Class IIa HDAC9 Controls Gonadotropin Releasing Hormone (GnRH) Neuronal Cell Survival and Movement. J Biol Chem 290:14045-56
Stratton, Matthew S; McKinsey, Timothy A (2015) Acetyl-lysine erasers and readers in the control of pulmonary hypertension and right ventricular hypertrophy. Biochem Cell Biol 93:149-57
Schuetze, Katherine B; McKinsey, Timothy A (2015) TNAP: a new player in cardiac fibrosis? Focus on ""Tissue-nonspecific alkaline phosphatase as a target of sFRP2 in cardiac fibroblasts"". Am J Physiol Cell Physiol 309:C137-8

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