Abstract 85: Cardiac Pathology Is Worsened by Loss of the Cell Junction Protein Claudin-5 and Improved by Claudin-5 Gene Therapy

Abstract

Claudin-5 is a cell-cell adhesion protein that plays established roles in the blood-brain barrier and cancer. We were the first to demonstrate that it plays a role in the heart with implications for heart failure and cardiomyopathy. Several animal models with cardiac pathology show reduced cardiac claudin-5 levels. Importantly, 60% of human heart failure patients show reduced levels of cardiac claudin-5, independent of changes in other cell junction proteins in the heart, supporting that the loss of cardiac claudin-5 has clinical relevance. To test our hypothesis that claudin-5 plays an important role in protecting the heart, we used mouse models to demonstrate whether circumventing reductions in cardiac claudin-5 is able to improve cardiac histology and physiology, and whether ablation of claudin-5 is able to induce cardiac pathology. We now show that maintaining cardiac claudin-5 levels using gene therapy (cldn5 transduction using an adeno-associated virus vector) significantly reduced cardiac pathology in mice which otherwise demonstrate heart failure and cardiomyopathy indicators. We also present preliminary evidence of the effects of knocking out the cldn5 gene specifically in cardiomyocytes using the inducible cre-loxP system.