It is widely recognized that pathological hypertrophy of the heart is associated with decreased fatty acid oxidation (FAO) and increased reliance on glucose utilization. Intensive research in the past decade has investigated whether the shift of substrate preference towards glucose is adaptive or maladaptive for the high energy demand of the heart. Evidence from these studies suggest that sustaining a high capacity for ATP synthesis via oxidative metabolism rather than the selection of substrates is critical for maintaining the energy supply to the heart during chronic stress. Prior studies by us and others have shown that increasing the oxidation of either glucose or fatty acids improves myocardial energetics and systolic function in chronically stress hearts. We thus ask whether decreased FAO affects mechanisms of heart failure beyond that for ATP production. It has been shown that decreased fatty acid oxidation in pathological hypertrophy is associated with decreased endogenous triglyceride turnover and accumulation of diglyceride and ceramide; in obesity animal models, cell death and pathological hypertrophy are also attributed to a mismatch of fatty acids uptake and oxidation which results in mitochondrial dysfunction, increased ROS and ER stress. In a recent study we sought to increase FAO by targeting the entry of long-chain fatty acids into the mitochondria via mCPT-1, the rate-limiting step. This was achieved by the deletion of acetyl-CoA carboxylase 2 (ACC2) which catalyze the formation of malonyl-CoA, an inhibitor of mCPT-1. Cardiac-specific deletion of ACC2 in mice (cKO) resulted in a 50% increase of FAO without affecting survival or cardiac function in the long term. Furthermore, it maintained normal metabolic profile and protected against the development of pathological hypertrophy and cardiac dysfunction during chronic pressure overload (TAC). Notably, the benefit in cKO is not limited to improved ATP supply from FAO as the cKO markedly decreased cardiac hypertrophy after TAC while increasing glucose uptake and utilization by overexpressing GLUT1 improved cardiac energetics and function but did not reduce hypertrophy. These observations have led us to hypothesize that sustaining fatty acid oxidation in the heart protects against the development of pathological hypertrophy during chronic stress. To address the question whether the above observations were due to the adaptive responses triggered by the deficiency of ACC2 at birth in the cKO we developed a mouse model with inducible deletion of ACC2 (iKO) in the heart. This model will also allow us to determine whether increasing FAO can arrest or regress existing pathological hypertrophy. Our preliminary data show that deletion of ACC2 in the adult mouse heart results in a similar increase of FAO as observed in cKO, and it suppressed the development of pathological hypertrophy by either angiotensin II (AngII) or diet-induced obesity. Therefore, our goal in the proposed studies are 1) to determine the mechanisms by which sustaining myocardial FAO protects against cardiac hypertrophy; 2) to test whether upregulating FAO can reverse the pathological remodeling and failure of the heart.
The hypertrophied and failing heart displays decreased fatty acid oxidation and increased reliance on glucose utilization. The proposed study seeks to determine the pathogenic mechanisms of impaired fatty acid oxidation and to test whether normalizing cardiac fatty acid oxidation arrests or reverses the pathological hypertrophy.
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