Abstract 8912: Pinch Proteins Are Essential for Cardiac Protein Kinase B Signaling
Integrin-linked kinase (ILK) is essential for cell maturation, migration and proper adhesion of the cardiac intercalated disks and costameres. It furthermore is as an essential component of the cardiac mechanical stretch sensor. Until now, the precise molecular function of ILK and its associated interaction partners are still unknown. To assess the cardiac function of ILK interacting PINCH proteins, we used a reverse genetics approach in zebrafish to identify and deplete the orthologs PINCH1 and PINCH2 by injection of morpholino antisense oligonucleotides. Depletion of either PINCH isoforms independently leads to instability of the ILK-PINCH-Parvin complex, loss of stretch-responsive gene expression and progressive heart failure. The impaired cardiac function in PINCH-deficient embryos can be explained by loss of Protein kinase B activity, since Akt/PKB phosphorylation at Serine 473 is significantly reduced in PINCH-morphants and overexpression of constitutively active PKB reconstitutes their cardiac function to almost normal values. Our data demonstrate an important role of PINCH proteins in maintaining cardiac contractility by stabilizing the IPP complex and thereby regulating Akt/PKB activity in the vertebrate heart.
- © 2011 by American Heart Association, Inc.