Autophagy in Metabolic Distress and Cardiac Function: Regulation by the HDAC-FoxO Axis Recent work has demonstrated that histone deacetylase [HDAC] inhibition [HDACi] is a promising strategy to target pathological cardiac hypertrophy, a process that can eventually lead to heart failure (HF). We have conducted studies in clinically relevant models of heart disease in vivo, demonstrating that pharmacological suppression of Class I and II HDAC activity inhibits, and even reverses, cardiac hypertrophy in response to pressure overload. At the same time, HDAC inhibition preserves ventricular size and systolic performance and diminishes interstitial fibrosis. In parallel work, we have also identified the transcription factor FoxO3 as a central element in the governance of cardiac catabolic pathways, especially the autophagy-lysosomal process. Furthermore, strong evidence has suggested that Class I and II HDACs (HDAC3, 5, and 9) regulate metabolic processes controlled by FoxO transcription factors (FoxO1 and 3). Moving forward, a leading hypothesis is that HDAC inhibition suppresses maladaptive autophagy and metabolic derangements in pressure overload and metabolic stress induced cardiomyopathy. HDAC inhibitors could target both maladaptive autophagy in hypertension and ameliorate metabolic stresses in diabetes. These agents can potentially turn into powerful ways in preventing and treat heart failure, especially in the current era of epidemic hypertension and diabetes. Also importantly, the HDAC inhibitor vorinostat is a FDA-approved and clinically well tolerated anti-cancer agent. Based on these data, we propose studies to decipher the mechanisms of HDAC-FoxO axis in regulating autophagy and metabolic pathways, a novel mechanism and therapeutic target of cardiomyopathy and HF. HYPOTHESES: HDAC inhibitors suppress cardiomyopathy-promoting maladaptive autophagy and metabolic derangements through regulating the function of FoxO transcription factors.
SPECIFIC AIMS :
Specific Aim 1. To define the role of HDACs and HDAC inhibition in regulating the function of FoxO transcription factors and autophagy in vitro. Specifi Aim 2. To characterize the role of Class I and II HDACs in regulating cardiomyocyte autophagy and the role(s) of FoxOs therein.
Specific Aim 3. To characterize the impact of HDACs (HDAC3, 5 and 9) and HDAC inhibitors on the function of FoxO1 and FoxO3 in models of metabolic stress. Studies proposed here will provide critical insight into how Class I and II HDACs regulate the function of FoxO1 and FoxO3 in the heart; how disturbance of the HDAC-FoxO pathway contributes to maladaptive autophagy, metabolic stress, cardiomyopathy, and pathological cardiac remodeling; how HDAC inhibition suppresses maladaptive autophagy and correct metabolic derangements by inhibiting the function of FoxO transcription factors under a variety of pathological conditions and protects cardiac function. At the same time, this work will move HDAC inhibition forward as a potentially promising therapeutic strategy in heart failure.
Studies proposed here will test whether HDAC inhibitors including FDA approved anti-cancer drug, Vorinostat, prevents and reverse pathological cardiac remodeling, cardiomyopathy secondary to various stresses including metabolic derangement and hypertension, thereby prevent the development of heart failure through suppressing FoxO transcription factors. We will characterize the HDAC-FoxO axis in the heart under various stresses. These studies will advance our understanding of autophagy as a novel mechanism and therapeutic target for the treatment of heart failure by HDAC inhibitors.
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