Collections > Electronic Theses and Dissertations > Cardiac Muscle RING Finger 1 Inhibits Adaptive Hypertrophic Remodeling Induced by IGF-1, Exercise, and Thyroid Hormone
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In the face of cardiac load, the heart responds by undergoing hypertrophy. Under pathological conditions, ventricular wall thickening cannot be maintained, impairing function (heart failure). In contrast, ventricular wall thickening in response to physiological stimuli does not impair cardiac function. Pathological and physiological hypertrophy are driven by distinct signaling pathways--while vasoactive factors induce the former, growth hormones induce the latter. Understanding the mechanisms through which heart growth is adaptive has recently become a goal of cardiac research, in the hopes of using this information in the discovery of therapies that promote restoration of the myocardium following injury (since an effective treatment for heart failure has yet to be developed). The purpose of this dissertation work is to describe new mechanisms by which physiological cardiac hypertrophy is regulated. Signaling pathways activated in the heart following physiologic stimuli are receptor tyrosine kinases (RTKs) and nuclear receptors (NRs), of which the IGF-1/Akt and TRalpha; pathways, respectively, are most understood. The work presented here establishes the striated muscle specific ubiquitin ligase, Muscle RING finger 1 (MuRF1) as a novel regulator of physiological cardiac hypertrophy through its ubiquitination of transcription factors. MuRF1 inhibits cardiomyocyte growth in response to IGF-1 and aerobic exercise stimulation by poly-ubiquitinating and promoting the degradation of c-Jun, recently discovered to drive transcriptional expression of genes coding for members of the IGF-1 signaling cascade. In contrast, MuRF1 mono-ubiquitinates TRalpha; thereby inhibiting TRalpha transcriptional activity and thyroid hormone (TH)-dependent cardiac hypertrophy. Furthermore, it is established here that mono-ubiquitination of TRalpha by MuRF1 induces TRalpha accumulation in the cardiomyocyte nucleus where TRalpha interacts with centrosome-associated protein 350 (CAP350). This inhibitory mechanism, while being established for other NRs, is completely novel for TRalpha and has never been described in the heart. Altogether, this dissertation contributes to the field of cardiac growth research by detailing the discovery of an inhibitor of not one, but two, signaling pathways that stimulate beneficial cardiac hypertrophy. Given that MuRF1 inhibits both IGF-1/Akt and TRalpha signaling, the activity of this ubiquitin ligase may be as efficacious target for new cardiac therapies by virtue of MuRF1's widespread influence on the cardiomyocyte.