The role of Quantitative variations in Connective Tissue Growth Factor gene expression in Cardiac Hypertrophy and Fibrosis

Connective tissue growth factor (CTGF) is a secreted, extracellular matrix (ECM) bound signaling molecule. While it stimulates maintenance and repair of the ECM, increased Ctgf gene expression is strongly associated with excess deposition of ECM in conditions of chronic organ injury and fibrotic diseases. High expression of Ctgf is also associated with cardiac fibrosis following chronic hypertension, myocardial infarction, and other cardiovascular diseases. Cardiac fibrosis is a major cause of heart dysfunction leading to heart failure, for which there is currently no effective treatments. The prevailing opinion in the field is that high expression of Ctgf causes fibrotic disease, and it has been proposed that inhibiting Ctgf expression will reduce fibrosis. This hypothesis, however, has not been directly tested. To test whether genetic variations in Ctgf expression modify hypertrophy or fibrosis, I have generated seven strains of mice that differ in their basal Ctgf expression levels across a 30-fold range, including utilizing a novel method of swapping the 3'UTR to achieve altered gene expression. Mice were naturally aged or treated with angiotensin II infusion or with transverse aortic constriction, to evaluate how altered basal Ctgf gene expression modifies cardiac hypertrophy and cardiac fibrosis related phenotypes. Contrary to the expectations, cardiac fibrosis in mice with higher basal Ctgf gene expression is increased only slightly or not at all, and mice with lower Ctgf gene expression had equal degrees of cardiac fibrosis compared to wild type mice. In contrast, both increased and reduced Ctgf gene expression mildly enhanced cardiac hypertrophy.. Furthermore, cardiac hypertrophy was not always increased in the presence of increased fibrosis, or visa versa, showing disconnects between these two phenotypes. Thus my experiments suggest that CTGF is not likely to be the master regulator of cardiac fibrosis, and that drug interventions to reduce Ctgf gene expression may not prevent fibrosis and could exacerbate cardiac hypertrophy. The allelic series of varying Ctgf gene expression generated as part of my work will be a useful tool to clarify the role of CTGF in other fibrotic diseases and could be used to further understand what other roles CTGF may play in human disease.Doctor of Philosoph