The role of connective tissue growth factor in diabetic cardiomyopathy

Connective tissue growth factor (CTGF) is a cysteine-rich secreted protein and known as a down stream mediator of transforming growth factor-[3 (TGF-B). The biological roles of CTGF include the regulation of cell proliferation, differentiation, survival, adhesion, extracellular matrix (ECM) accumulation and angiogenesis. Diabetic cardiomyopathy (DCM) is characterised by interstitial fibrosis, cardiomyocyte hypertrophy and apoptosis. CTGF is strongly implicated in the pathogenesis of a variety of fibrotic disorders, including renal fibrosis in diabetes. However, the role of CTGF in DCM is still less clear. Cardiomyocytes occupy 70-80% of the mass of myocardium and myocytes may play an important role in the development of DCM. It is unknown if CTGF has adverse effects in cardiomyocytes or whether CTGF plays a role in mediating the documented adverse cardiomyocyte changes that are induced by high glucose and lipids levels. The central hypothesis of this thesis is that CTGF plays an important role in the pathogenesis of DCM, including in hypertrophy, apoptosis, inflammation and fibrosis. The main aims of this study are to: i) determine the role of CTGF on hypertrophy and apoptosis in cardiomyocytes; ii) determine whether CTGF mediates the adverse effects of hypertrophy and apoptosis by high glucose and free fatty acid (FFA), and whether CTGF mediates these adverse effects through the cellular tyrosine kinase receptor A receptor (TrkA) pathway; iii) examine the effects of CTGF on fibrosis and inflammation, and whether these effects by CTGF are TGF-B and/or TrkA dependent in cardiomyocytes; iv) elucidate the role of CTGF in cardiac fibrosis in cultured cardiac fibroblasts; and v) compare the pathogenesis in animal model of diabetic and normal rat heart, include gene regulation of CTGF, as well as hypertrophy, fibrosis and inflammation end-points and apoptosis in vivo