O-GlcNAc Signaling in Heart Failure

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DESCRIPTION (provided by applicant): Cardiac hypertrophy arises from multiple, often idiopathic, origins. Pressure overload induces cardiomyocyte hypertrophy and eventually can lead to heart failure. The induction of pathologic hypertrophy involves the transcriptional reprogramming of metabolic machinery. Thus, hypertrophy involves a metabolic disturbance leading to cardiac dysfunction. Glucose represents the quintessential substrate for metabolism, albeit to a limited extent in the heart. Less than 5% of intracellular glucose is shunted to accessory pathways, such as Hexosamine Biosynthetic Pathway, which forms the monosaccharide donor for the post-translational modification known as O-linked-2-N- acetylglucosamine (O-GlcNAc). Many of the signaling pathways involved with the development of cardiac hypertrophy, particularly during the transition to failure, have been elegantly elucidated by other laboratories. The present proposal will unravel the contribution of O-GlcNAc signaling to the development of hypertrophy, in addition to understanding a potential role in pressure overload-induced heart failure. PGC-11 is recognized as a regulator of metabolism and its loss can aggravate pressure overload- induced heart failure. Nothing is currently known about the relationship between O-GlcNAc signaling and PGC-11 during the development of hypertrophy and heart failure. One goal of the present study is to investigate the mechanisms through which O-GlcNAc signaling participates in myocyte response to hypertrophy by focusing on the transcriptional activity of PGC-11. This proposal will identify the role O-GlcNAc signaling in the development of cardiomyocyte hypertrophy and heart failure by: 1) Determining what changes occur in O-GlcNAc signaling in the myocardium during hypertrophy. 2) Ascertaining whether O-GlcNAc signaling is essential during hypertrophy. 3) Identifying the influence of O-GlcNAc signaling on PGC-11 during hypertrophy. 4) Elucidating the impact of altered O-GlcNAc signaling at the mitochondrial level during hypertrophy. The PI's hypothesis is that O-GlcNAc signaling is augmented during the development of hypertrophy, and such augmentation of is maladaptive. Furthermore, the PI posits that O-GlcNAc signaling suppresses PGC-11, and, such changes are instrumental in the development of the hypertrophied and failing phenotypes. Findings from such mechanistic studies will provide novel insights into the pathophysiologic mechanisms operative during the development of hypertrophy and in the failing myocardium. PUBLIC HEALTH RELEVANCE: One limiting factor in identifying more efficacious treatments for heart failure is our lack of understanding of the initiation and progression of the disease, particularly as it relates to metabolic signaling. The present series of studies will provide keen insights into mechanisms of cardiac growth, metabolism, and the development of pressure overload induced hypertrophy, which will lay the groundwork for the creation of new therapeutics.