Metabolic Remodeling in the Hypertrophic Heart Fuel for Thought
DPhil, Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, 703 19th St S, ZRB 308, Birmingham, AL 35294. .Circulation Research (Impact Factor: 11.02). 08/2012; 111(6):666-8. DOI: 10.1161/CIRCRESAHA.112.277392
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ABSTRACT: It has become common sense that the failing heart is an "engine out of fuel". However, undisputable evidence that, indeed, the failing heart is limited by insufficient ATP supply is currently lacking. Over the last couple of years, an increasingly complex picture of mechanisms evolved that suggests that potentially metabolic intermediates and redox state could play the more dominant roles for signaling that eventually results in left ventricular remodeling and contractile dysfunction. In the pathophysiology of heart failure, mitochondria emerge in the crossfire of defective excitation-contraction coupling and increased energetic demand, which may provoke oxidative stress as an important upstream mediator of cardiac remodeling and cell death. Thus, future therapies may be guided towards restoring defective ion homeostasis and mitochondrial redox shifts rather than aiming solely at improving the generation of ATP.
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ABSTRACT: The cardiovascular system is capable of robust changes in response to physiologic and pathologic stimuli through intricate signaling mechanisms. The area of metabolism has witnessed a veritable renaissance in the cardiovascular system. In particular, the post-translational β-O-linkage of N-acetylglucosamine (O-GlcNAc) to cellular proteins represents one such signaling pathway that has been implicated in the pathophysiology of cardiovascular disease. This highly dynamic protein modification may induce functional changes in proteins and regulate key cellular processes including translation, transcription, and cell death. In addition, its potential interplay with phosphorylation provides an additional layer of complexity to post-translational regulation. The hexosamine biosynthetic pathway generally requires glucose to form the nucleotide sugar, UDP-GlcNAc. Accordingly, O-GlcNAcylation may be altered in response to nutrient availability and cellular stress. Recent literature supports O-GlcNAcylation as an autoprotective response in models of acute stress (hypoxia, ischemia, oxidative stress). Models of sustained stress, such as pressure overload hypertrophy, and infarct-induced heart failure, may also require protein O-GlcNAcylation as a partial compensatory mechanism. Yet, in models of Type II diabetes, O-GlcNAcylation has been implicated in the subsequent development of vascular, and even cardiac, dysfunction. This review will address this apparent paradox and discuss the potential mechanisms of O-GlcNAc-mediated cardioprotection and cardiovascular dysfunction. This discussion will also address potential targets for pharmacologic interventions and the unique considerations related to such targets.