Characterizing intracellular signaling mechanisms involved in the progression of cardiac hypertrophy and failure: involvement of JAK/STAT and MAPK pathways

Dominic Ng

Research output: ThesisDoctoral Thesis

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Abstract

[Truncated abstract] The innate ability of the heart to compensate for an increase in workload as a result of disease or injury, through an increase in size and mass is known as cardiac hypertrophy. The hypertrophy of the heart compensates for an increase in workload with an increase in cardiac output. However, excessive hypertrophy can result in cardiac dysfunction and substantially increases the risk of cardiac failure and mortality. The molecular mechanisms that regulate the development of cardiac hypertrophy and cardiac failure are not entirely understood. Traditionally, the G-protein Coupled Receptor (GPCR) and the downstream Mitogen-Activated Protein Kinase (MAPK) family of proteins have been implicated. However, elevated circulating and ventricular levels of several classes of cytokines also suggested that signaling by the downstream effectors of cytokine receptors, such as the Signal Transducers and Activators of Transcription (STATs), may be important. The aim of this thesis was, therefore, to characterize the involvement of MAPK and STAT pathways in regulating cardiac hypertrophy and cardiac failure. A function for MAPK and STAT signaling in regulating cardiac hypertrophy stimulated by the inflammatory cytokine IL-1Β was initially defined in primary cultures of neonatal rat cardiac myocytes. In this study, it was demonstrated that the chemical inhibition of ERK or p38MAPK was sufficient to inhibit IL-1Β-stimulated ANF expression. In contrast, simultaneous inhibition of both ERK and p38MAPK was required to ablate the hypertrophic morphology of cardiac myocytes treated with IL-1Β. These results demonstrated differential signaling from the MAPK isoforms in regulating the gene expression and morphological components of cardiac hypertrophy. In addition, it was revealed that IL-1Β treatment resulted in a delayed response (>60 min) in STAT3α tyrosine phosphorylation, which was subsequently shown to require the initial rapid activation of either ERK or p38MAPK. IL-1Β-stimulated STAT3 phosphorylation was also dependent on the de novo synthesis of secondary signaling molecules. The ablation of the STAT3 tyrosine phosphorylation by the inhibition of ERK or p38MAPK activity, correlated with the attenuation of IL-1Β-stimulated ANF expression, suggesting that signaling through STAT3α may be involved in regulating gene expression associated with IL-1Β cardiac hypertrophy
Original languageEnglish
QualificationDoctor of Philosophy
Publication statusUnpublished - 2003

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