Heart disease is unsurpassed as the greatest noninfectious health hazard ever to confront the human race. It is estimated that five million Americans have heart failure, a syndrome with 5-year mortality of ?50%7. For some years, heart failure has remained a leading cause of death in industrialized nations, and the epidemic is rapidly expanding to include the developing world. Accordingly, heart failure, the end-result of pathological cardiac remodeling, is responsible for a huge societal burden of morbidity, mortality, and cost. Stress-induced hypertrophic growth of the myocardium is an integral step in the pathogenesis of many forms of heart failure. This hypertrophic growth process is complex, involving more than just increases in myocyte size and heightened sarcomeric organization. Rather, a shift toward glycolytic metabolism, alterations in Ca2+ storage and handling, changes in contractility, and reactivation of a fetal gene program are seen18. Importantly, some evidence suggests that suppression of pathological cardiac hypertrophy per se is a viable target for therapeutic intervention17, 19. Indeed, preclinical studies have shown that attenuation of load-induced hypertrophy is well tolerated, and ventricular dilation and decompensation do not occur17, 19, and 20. Correlative studies in heart disease patients support this contention21. To pursue suppression of pathological cardiac hypertrophy as a therapeutic intervention, studies to define proximal triggers are required. FoxO transcription factors, two isoforms of which are expressed at high levels in cardiomyocytes (FoxO1, FoxO3) govern a wide range of key molecular and cellular events, including responses to stress, cell viability, cell-cycle progressio, protein degradation and metabolic control8. Recently, we uncovered two novel, previously unappreciated pathways governed by FoxO1 which participate importantly in cardiac growth and function: a) FoxO1-dependent control of Vcam1 expression, and b) FoxO1-dependent control of intracellular thyroid hormone homeostasis. Studies laid out here are significant in that they probe mechanisms which are previously unrecognized and for which we have strong evidence of pathophysiological relevance. Additional benefits from the proposed work will accrue to the fields of FoxO biology and cardiac remodeling, as this work is expected to enable subsequent thinking and research, allowing us and others to build on a growing body of knowledge. Benefit will also accrue to other areas, such as cell adhesion molecules, thyroid hormone biology, intracellular deiodinases, and FoxO-dependent transcription. For all these reasons, work proposed here is highly significant and expected to provide concrete benefit in decreasing disease-related morbidity and mortality. As such, this work is consistent with NIH's mission to protect and improve health.

Public Health Relevance

Heart attack - myocardial injury from ischemia followed by reperfusion - is a leading cause of death. Yet, we have no therapies whatsoever targeting the reperfusion injury component of the process, even though it accounts for 50% of the pathological response. We propose to dissect two novel pathways downstream of the transcription factor Fox01, which preliminary evidence suggests contribute significantly to the maladaptive response and raise the prospect of therapeutic targeting of these novel pathways for clinical benefit.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Adhikari, Bishow B
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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