ConCOEUR: Unveiling the impact of Connexin43 (Cx43)-mediated gene expression at the crossroads of aortic valve stenosis and left ventricle hypertrophy

Overview

Project Summary

 Aortic valve stenosis (AVS) is the most prevalent valvular heart disorder and the third most common cause of cardiovascular disease in the western world. AVS is characterized by progressive narrowing, fibrosis and calcification of the aortic valve (AV). Traditionally viewed as a mere valve disorder, AVS is now recognized as a central cause of left ventricle hypertrophy. Aortic valve replacement is the standard of care for severe symptomatic AVS patients, improving quality of life and long-term survival. However, most patients have a long asymptomatic period, which hampers timely diagnosis and intervention. Hence, it is vital to identify novel therapies to hinder AVS and left ventricle dysfunction, aiming to improve patient prognosis.

For decades, Connexin43 (Cx43), the main gap junction (GJ) protein, has been associated with cell-cell communication. New compelling and revolutionizing evidence ascribe non-canonical roles to Cx43 upon other biological processes, including regulation of gene expression. Whether these effects are related to the previously reported presence of Cx43 in the cell nucleus remains unknown. Hence, the long-term goal of this proposal is to unveil the function of nuclear Cx43 and its impact on cardiovascular diseases. Particularly, we hypothesize that injury-induced accumulation of nuclear Cx43 regulates the expression of genes that drive AVS progression and cardiac hypertrophy. To achieve this, ConCOEUR is grounded on a cohesive and interdisciplinary translation effort to connect basic mechanistic knowledge with pre-clinical animal models that will ultimately be related to human heart diseases, aiming to design novel therapeutic strategies to improve clinical outcomes and reduce AVS burden.

Main Goals

1)    Evaluate the role of Cx43 on the fibro-calcification mechanisms of the aortic valve

2)    Establish a correlation between Cx43 levels and reverse remodeling of the heart after surgical aortic valve replacement in aortic stenosis patients

Project Details