Neuronostatin, connective tissue growth factor and glycogen synthase kinase 3β in cardiac physiology and disease.

Cardiovascular diseases are the leading cause of death in Western countries and new, more targeted therapeutical approaches are needed. The aim of my thesis was to increase understanding of the signaling pathways regulating progression of cardiac remodeling from myocardial infarction injury and cardiac hypertrophy to heart failure. In these preclinical studies, I focused on the factors regulating cardiomyocyte survival, hypertrophy and extracellular matrix modulation; neuronostatin (NST), connective tissue growth factor (CTGF), and glycogen synthase kinase 3β (GSK3β). I found that NST has an attenuating effect on left ventricular contractility in isolated perfused rat heart and it also reduced survival of the cultured cardiomyocytes. Therapy with a CTGF monoclonal antibody improved recovery after myocardial infarction in mice. Phosphorylation of the GSK3β S389 site was cardioprotective and antihypertrophic in cultured cardiomyocytes. I also dissected the cellular signaling mechanisms regulated by these factors. This study reveals novel biological functions and signaling mechanisms for these factors and may eventually lead to development of targeted therapies to decrease and prevent cardiac injury.