HGF-mediated modulation of Connexin 43 in cardiac cells

Connexin43 (Cx43) is the predominant isoform expressed in the Gap Junctions (GJ) of the working ventricular myocardium. Six connexin molecules complex to form a connexon hemichannel, which, when inserted into the plasma membrane, can bind with a hemichannel on an opposing cell, creating an intercellular channel that connects the cytoplasms of both cells and allows electrical and metabolic communication between cardiomyocytes. GJ are concentrated at intercalated discs, discrete regions of cardiomyocyte-cardiomyocyte couplingin the heart, where they intimately interact with adherens junctions. Recent works have demonstrated the importance of Cx43 in ischaemic and pharmacological preconditioning, and that this protection does not depend on GJ intercellular communication. In the present study, we investigated the role of HGF/Met tyrosine kinase pathway, known to exert cardioprotective effects, in the modulation of Cx43. We have analyzed Cx43 protein levels and phosphorylation changes in the H9c2 cell line of rat embryonal cardiomyoblasts, stimulated with HGF for various length of time. HGF stimulation activates PKC epsilon and Erk1,2 signaling. Concomitantly, it upregulates Cx43 protein levels and its phosphorylation on Ser368, a PKC targeting site in Cx43. Furthermore, HGF stimulation of H9c2 cells induces accumulation of intracellular Cx43 and colocalization with mithocondria. The elucidation of the regulation, biological meaning and pathophysiological relevance of the intracellular localization of Cx43 and, more generally, of the functions of this protein, unrelated to GJ-mediated intercellular communication, represents a new and exciting field of research with potentially important biomedical applications in cardiovascular disease