Role of Claudin-5 in Cardiac Remodeling during Heart Failure

Duchenne Muscular Dystrophy (DMD) is fatal, progressive, X-linked disorder characterized by lack of dystrophin production leading to skeletal muscle degeneration, respiratory distress, and cardiomyopathy. Nearly all patients who suffer from DMD develop cardiomyopathy by their early 20s. Studies in the Rafael-Fortney lab showed that reduced expression of the tight junction protein claudin-5 at the cardiomyocyte lateral membrane near the extracellular matrix (ECM) is linked to cardiomyopathy in dystrophin/utrophin double knockout (dko) mice. This led the Rafael-Fortney lab to find that 60% of human heart failure explant samples from varying etiologies also lacked claudin-5. Our current study examines the relationship between claudin-5 in the heart and the ability of cardiomyocytes to bind to ECM proteins. This relationship is interesting because down-regulation of claudin-5 may reduce adhesion to ECM proteins which permits cardiac remodeling associated with heart failure to occur. We hypothesize that the lack of claudin-5 plays a role in the adhesion ability of cardiomyocytes.  Our preliminary data suggests that cardiomyocytes taken from wild type mice, which express regular levels of claudin-5, have a greater ability to bind to ECM proteins compared to dko mice. The comparison with pathological changes in ECM protein composition will be correlated with binding properties of cardiomyocytes to determine in vivo claudin-5 ECM changes.  With support from this hypothesis, the mechanism through which claudin-5 increases adhesion ability will be explored. If claudin-5 is found to have an effect on the binding property of cardiomyocytes it could represent a novel target for a variety of cardiomyopathies.