Effects of mechanical forces and mediators of hypertrophy on remodeling of gap junctions in the heart.

Abstract

This review article focuses on remodeling of gap junctions in response to chemical mediators of ventricular hypertrophy, mechanical forces, and alterations in cell-to-cell adhesion. Signaling mediated by mechanical forces is likely to be involved in the upregulation of cardiac gap junctions during the early phase of cardiac hypertrophy and the subsequent downregulation in cardiac failure. Several signaling pathways involving cAMP, angiotensin II, transforming growth factor-beta, vascular endothelial growth factor, and integrin-mediated regulators have been shown to affect expression of gap junction proteins. However, a comprehensive view of regulation of gap junction trafficking, synthesis, and degradation is still lacking. In addition to gap junction regulation by extracellular mechanical forces, there is a close relation between gap junctions and adhesion junctions and their linkage to the cytoskeleton. This can be inferred from experiments on neoformation of cell-to-cell coupling, concomitant upregulation of adherens and gap junctions after mechanical stretch, and human cardiomyopathies caused by genetic defects in cell-cell adhesion junction proteins. The molecular mechanisms responsible for the interaction between mechanical and functional cell-to-cell coupling remain to be elucidated.