DELVING INTO THE HEART OF THE MATTER: UNDERSTANDING THE ASSOCIATIONS BETWEEN TGF-β, CTGF AND EARLY MYOCARDIAL CHANGES IN ANGIOTENSIN-II INDUCED MYOCARDIAL FIBROSIS

Abstract

Myocardial fibrosis is the common pathophysiological complication associated with diastolic heart failure. It is characterized by excess extracellular matrix (ECM) protein deposition, which contributes to increased ventricular wall stiffness and impaired relaxation. Transforming growth factor-β (TGF-β) and connective tissue growth factor (CTGF) are well-known to be fibrotic mediators associated with myocardial fibrosis. These cytokines, among others, act on resident and infiltrating cells, such as monocytes and fibroblasts, after cardiac injury or stress and alter cell phenotype and, consequently, the myocardial environment in an effort to repair the injured site. In this thesis, the early molecular and cellular changes associated with hypertension-induced myocardial fibrosis are explored using a model of continuous Angiotensin II (Ang-II) infusion in mice. By using a TGF-β trap able to sequester and neutralize active TGF-β, we demonstrated that TGF-β activity plays a role in CTGF transcript upregulation via TGF-β/Smad dependent signaling prior to cell infiltration after Ang-II infusion. We suggest that this is likely due to latent TGF-β activation in resident cardiac cells, illustrating the close relationship between TGF-β and CTGF implicated in fibrosis. Additionally, monocytes/Mϕs are shown to be key orchestrators of inflammatory and subsequent fibrotic response after myocardial injury. We demonstrated a pro-inflammatory shift in monocyte/Mϕ phenotype in the myocardium and spleen, as defined by Ly6Chigh expression after 3 days of Ang-II infusion, which may be heavily influenced by early inflammatory and fibrotic mediators produced by myocardial resident and infiltrated cells. This study opens a path towards opportunities for future studies to bridge the knowledge gap between associated mechanisms and the development of myocardial fibrosis.