Regulation of the load-induced response in heart. Roles of activating transcription factor-3, GATA4, phenylephrine regulated factor 1 and BRG1/BRM associated factor 60c in cardiac fibrosis

Heart failure is commonly preceded by cardiac remodeling processes which include structural and functional alterations initiated in response to pathophysiological stimuli. Pathological ventricular remodeling is characterized by hypertrophic growth of cardiac myocytes alongside increased fibrosis, cell death and inflammation. An important component of the pathological response is extracellular matrix (ECM) remodeling. Excessive accumulation of ECM and scarring reduces compliance of the myocardium and impairs left ventricular (LV) function. Transcription and epigenetic factors involved in embryonic cardiogenesis are re-employed during pathophysiological remodeling by eliciting changes in gene expression programs that will determine the cellular adaptive responses in the myocardium. In animal and cellular models of normal and stressed heart, gain/loss of function studies were used to investigate the actions of transcription factors activating transcription factor-3 (ATF3), phenylephrine regulated factor 1 (PEX1) and GATA binding factor 4 (GATA4), and chromatin remodeling factor BAF60c in the LV remodeling process.

Activation of ATF3 in cardiomyocytes upregulated the expression of pro-survival factors and downregulated the expression of pro-fibrotic plasminogen activator inhibitor-1 (PAI-1) and interleukin-6 (IL-6). PEX1 induced fibrosis in adult rat heart and promoted the expression of genes associated with ECM remodeling in vivo and in cultured cardiac fibroblasts, but not in myocytes. Modulation of MMP9 expression is suggested as a mechanism for PEX1 to induce activation of myofibroblasts. GATA4 overexpression in a hypertension model mitigated the remodeling response by reducing apoptosis and downregulating genes associated with fibrosis and hypertrophy. Phosphorylation at Ser105 of GATA4 binding region was found to be critical for GATA4 cardioprotective effects. BAF60c expression was induced after myocardial infarction and upregulated pro-fibrotic and pro-hypertrophic genes in cultured fibroblasts and cardiomyocytes.

Overall, this PhD thesis sheds light on the roles of ATF3, PEX1, GATA4 and BAF60c particularly in the fibrotic facet of myocardial remodeling, alongside their involvement in the hypertrophic response.