Speaker Dr Giancarlo Forte, Senior Lecturer, School of Cardiovascular and Metabolic Medicine & Sciences, KCL

Title Pathological mechanosensing in the human heart

Host Elisabetta Brunello

 

Abstract The onset and progression of cardiac pathologies are paralleled by continuous local extracellular matrix (ECM) remodelling. This process serves as a compensatory strategy for tissues to cope with the altered conditions. Cardiomyocytes respond to the ensuing biomechanical stress by adapting their transcriptional and post-transcriptional landscape.

Our group is interested in dissecting how modifications in the mechanics and nanostructure of the heart pathological ECM impact on cardiac cell function.

We first demonstrated that the aberrant activation of mechanosensitive Yes Associated Protein (YAP) in response to mechanical stress alters the assembly of focal adhesions and generates a positive loop perpetuating ECM remodelling. This observation held true in different biological systems spanning from the cardiovascular system to tumours.

Lately we furthered our understanding of the molecular basis of pathological mechanosensing when we described the phenomenon of mechanosensitive mRNA splicing in cardiomyocytes. Our experimental data in fact show how the pathological remodeling of ECM in the failing heart directly affects the expression and function of RNA binding proteins in cardiomyocytes. Finally discovered in other cell systems like pluripotent stem cells, mechanosensitive splicing represents a novel layer of mechanosensing responsible for finely tuning the expression of genes involved in development and disease.