Recent studies point to the importance of enzymes that control histone acetylation as stress- responsive regulators of gene expression in the heart. These enzymes function as nuclear integrators that couple diverse upstream signals to govern gene expression. Pharmacological suppression of histone deacetylases (HDACs) is emerging as a promising therapeutic approach in the field of oncology. In this proposal, we will explore HDAC inhibition as a novel therapy in heart disease. Suppression of HDAC activity blunts hypertrophic growth of cardiac myocytes in culture. Preliminary results from our lab with 2 broad-spectrum HDAC inhibitors document significant suppression of hypertrophy in a clinically relevant, aortic banding model. Importantly, despite persistence of afterload stress, HDAC inhibitor-mediated blunting of hypertrophic growth was well tolerated, ventricular size and systolic performance were preserved, and interstitial fibrosis was diminished. Thus, HDAC inhibition (HDACi) appears to blunt pathological growth of the heart. We hypothesize that HDAC suppression with these (and other) small molecules may be an important therapeutic approach in heart disease and worthy of further investigation. Here, we propose studies in animal models of pressure-overload hypertrophy and failure that are designed to determine the utility of HDAC suppressive therapy.
In Aim 1, we will study a limited number of structurally diverse HDAC inhibitors to confirm and extend our preliminary studies, determine the effects of these compounds on clinical, functional, and molecular endpoints, and examine the generalizability of this approach to antihypertrophic therapy.
In Aim 2, we will examine selected molecular mechanisms we hypotheisze contribute to the salutary effects of HDACi, specifically 1) potentiation of Foxo activity, and 2) suppression of MHC isoform switching.
In Aim 3, studies are proposed to define molecular mechanisms that preserve systolic performance, including changes in intracellular Ca2+ homeostasis and the expression and phosphorylation of proteins involved in Ca2+ handling.
In Aim 4, we will decipher mechanisms governing diminished fibrosis in HDAC inhibitor-treated hearts, testing the effects of HDAC inhibitors on the biosynthesis and processing of collagens in cultured cardiac fibroblasts and in vivo. Studies proposed here will explore the 3 major effects of HDAC inhibitors observed in our preliminary studies of pressure-stressed myocardium: attenuated hypertrophic growth, preserved systolic performance, and diminished fibrogenesis. Together, these studies will provide important insights regarding the utility of HDACi pharmacotherapy as a novel antihypertrophic strategy.
|Li, Dan L; Wang, Zhao V; Ding, Guanqiao et al. (2016) Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification. Circulation 133:1668-87|
|Hu, Ming Chang; Shi, Mingjun; Cho, Han Jun et al. (2015) Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol 26:1290-302|
|Cao, Dian J; Lavandero, Sergio; Hill, Joseph A (2015) Parkin Gone Wild: Unbridled Ubiquitination. Circ Res 117:311-3|
|Wang, Zhao V; Hill, Joseph A (2015) Protein quality control and metabolism: bidirectional control in the heart. Cell Metab 21:215-26|
|Daniels, James D; Hill, Joseph A (2015) Funny and late: targeting currents governing heart rate in atrial fibrillation. J Cardiovasc Electrophysiol 26:336-8|
|Pedrozo, Zully; Criollo, Alfredo; Battiprolu, Pavan K et al. (2015) Polycystin-1 Is a Cardiomyocyte Mechanosensor That Governs L-Type Ca2+ Channel Protein Stability. Circulation 131:2131-42|
|Wang, Zhao V; Deng, Yingfeng; Gao, Ningguo et al. (2014) Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway. Cell 156:1179-1192|
|Xie, Min; Kong, Yongli; Tan, Wei et al. (2014) Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation 129:1139-51|
|Cao, Dian J; Hill, Joseph A (2014) Copper futures: ceruloplasmin and heart failure. Circ Res 114:1678-80|
|Li, Dan L; Hill, Joseph A (2014) Cardiomyocyte autophagy and cancer chemotherapy. J Mol Cell Cardiol 71:54-61|
Showing the most recent 10 out of 77 publications