Thursday, May 9, 2024
5/9/2024
Project summary/abstract Chronic diseases including heart failure (HF) often present with thyroid dysfunction. Evidence from animal and human studies of HF provide strong evidence that low thyroid hormones (TH) contribute to poor prognosis and that TH treatment improves measures of cardiac function. Experimental studies of heart diseases due to ischemia and hypertension, or diabetic cardiomyopathy, all induce low cardiac tissue T3 (bioactive TH) concentrations that we propose is the primary cause of myocyte dysfunction. T3 regulates many cellular processes including transcription of cardiac genes regulating calcium and contractility, cell survival, growth, adrenergic and ion channel activities. We hypothesize that T3 regulates T-tubule (TT) structures in cardiomyocytes, and that impaired T3 signaling leads to adverse TT remodeling and contractile dysfunction. This concept is supported by recent studies indicating an essential requirement of THs in the development of a functioning TT network in the transition from structurally immature neonatal to adult cardiomyocytes. Advancements in super-resolution imaging have confirmed that adverse remodeling of TT occurs in cardiomyocytes from patients and animal models of HF leading to impaired excitation- contraction (EC)-coupling. Our preliminary data show that cardiomyocyte TT periodicity is significantly reduced in MI-induced heart failure and TH-deficient animal models, causing slower calcium kinetics and contractility. The overarching goal of this work is to provide rigorous scientific evidence to support a therapeutic benefit in normalizing TH function in patients with heart failure. To accomplish this goal, we propose to study two disease models of thyroid dysfunction: (1) heart failure induced by myocardial infarction (MI), and (2) TH-deficiency produced by chemical (PTU) inhibition of TH production. In the HF model, oral treatment with replacement-dose T3 will be initiated immediately after MI and continued for 16 weeks. Ca2+ transients and contractility will be recorded from isolated ventricular myocytes, and T3 effects on TT remodeling will be assessed by confocal microscopy. We will use multi-wavelength super-resolution single-molecule imaging that is currently the best approach to quantify potential T3-induced changes in distribution of Ca2+ handling proteins (Ryanodine receptors, L-type Ca2+ channels, Bridging Integrator-1, Junctophilin-2). In the TH-deficient model, effects of short-term T3 treatment alone on TT periodicity, clustering of Ca2+ proteins and contractile function will be similarly assessed. Interrogation of the molecular mechanisms underlying the TT remodeling responses to T3 will involve cultured adult ventricular myocytes, and expressed gene studies including RNAseq approaches. Results from this study have the potential to advance treatment options for the patient with HF presenting with low serum THs. Support of this proposal by REAP will promote the research environment at NYIT, and provide opportunities for our students to participate in clinically relevant research that may change the course of patient care.
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