Cardiac hypertrophy occurs when cardiomyocytes are continuously exposed to stresses, such as mechanical stretch or neurohumoral stimulation. The enlargement is characterized by changes in signaling, gene expression and electrophysiology that confers short-term benefits; over time, however, the plasticity of the cardiac muscle in response to these pathological insults predispose individuals to heart failure and mortality. Hence, there is an urgent need to improve our understanding of the molecular events implicated in the development of cardiac hypertrophy and of the progression of heart failure in order to identify new therapeutic targets. Although numerous genetic and pharmacological studies have demonstrated that increased signaling by cellular oxidants were intimately involved in the progression of cardiac hypertrophy, the molecular mechanisms whereby oxidants contribute to the progression of hypertrophy are largely unknown. In order to shed light on these mechanisms, our efforts have focused on protein tyrosine phosphatases (PTPs) and their distinctive ability to be specifically and reversibly regulated by redox signaling. This research proposal builds upon our novel observations that oxidation and inactivation of protein tyrosine phosphatase 1B (PTP1B) leads to phosphorylation and inactivation of its substrate argonaute 2 (Ago2), a key mediator of the biological functions of microRNAs (miRNAs) in the hypertrophying myocardium. Preliminary data revealed in this proposal show that PTP1B inactivation by cellular oxidants and by conditional, cardiomyocyte-specific gene knockout (PTP1B cKO) results in phosphorylation and inactivation of its substrate Ago2, left ventricular hypertrophy and systolic dysfunction in a thyroid-hormone (T3)-dependent manner. Our in vivo data reveal an important relationship between PTP1B inactivation and T3 signaling in cardiac hypertrophy that occurs as a consequence of: defective miRNA-mediated repression of thyroid-hormone receptor-associated protein 1 (THRAP1, known as MED13); a miRNA-independent increase in thyroid-hormone receptor ?1 (TR?1) expression and; a TR?1-interaction with p85 the regulatory subunit of phosphatidyl-inositol 3 kinase (PI3K) when PTP1B is inactivated. These data are consistent with the known T3 regulation of myocardial contractility and systolic function. We hypothesize that PTP1B inactivation prevents post-transcriptional regulation by Ago2-miR-208b and profoundly alters T3 signaling in cardiac hypertrophy. We propose that therapeutic compensation of PTP1B activity will be cardioprotective. We will test our hypothesis by investigating 1) the interplay between PTP1B and thyroid-hormone signaling in cardiac hypertrophy; 2) the therapeutic compensation of PTP1B activity in vivo. Understanding how PTP1B integrates redox signaling to regulate thyroid hormone signaling will facilitate the development of novel therapeutic strategies to control targeted protein expression and activation in cardiac pathologies.
Heart failure is a syndrome of major public heath significance. It is estimated that >6.5 million US citizens suffer from heart failure, with about one million new cases diagnosed annually. A better understanding of the cellular mechanisms that control cardiac remodeling, including pathological myocyte hypertrophy, should yield better therapeutic regimens with decreased mortality.
