Abstract 11732: The Z-Disc Proteoglycan Syndecan-4 Regulates Mechanical Stress-Induced Calcineurin-NFAT Signaling in Cardiomyocytes
Mechanical stress is regarded as an important stimulus for the hypertrophic response in cardiomyocytes, but the signaling systems involved are still unknown. We have previously shown that syndecan-4, a transmembrane proteoglycan localized to the cardiomyocyte Z-discs, is essential for development of concentric hypertrophy following pressure overload. We here demonstrate that syndecan-4, which connects the extracellular matrix to the cardiomyocyte cytoskeleton, regulates mechanical stress-induced calcineurin-Nuclear Factor of Activated T-cell (CnA-NFAT) signaling in cardiomyocytes. Syndecan-4 protein levels were increased 1.7-fold in biopsies from hypertrophic human myocardium obtained peroperatively from aortic stenosis patients. When introduced as a gene or cell-permeable peptide (gain of function), syndecan-4 activated NFATc4 in cardiomyocytes in vitro. To examine whether mechanical stimuli activate CnA-NFAT through syndecan-4, cardiomyocytes from syndecan-4 KO-NFAT-luciferase reporter mice were subjected to cyclic mechanical stretch (10%, 1Hz). NFAT activation was increased 11.6-fold by 24 hrs of mechanical stretch in NFAT-luciferase cardiomyocytes. Importantly, NFAT activation was only 1.6-fold increased following stretch in syndecan-4 KO-NFAT luciferase cardiomyocytes, i.e. significantly lower than in the NFAT-luciferase cardiomyocytees subjected to the same stretch protocol. Similar data were obtained in stretched syndecan-4 KO and wild-type cardiomyocytes as assessed by NFATc4 phosphorylation. Hypertrophy, as measured by protein synthesis, as well as NFAT activation, assessed by NFAT-luciferase activity and phosphorylation, were reduced in syndecan-4 KO cardiomyocytes subjected to autonomous growth, compared to wild-type controls. In vivo, we showed that mechanical stress following aortic banding of syndecan-4 KO mice induced less activation of NFAT as assessed by NFATc4 phosphorylation and expression of the NFAT target gene RCAN1-4, compared to wild-type controls. Conclusively, our data indicate that in cardiomyocytes of a pressure-overloaded heart, mechanical stimuli are sensed by the Z-disc proteoglycan syndecan-4 which activates pro-hypertrophic CnA-NFAT signaling.
- © 2011 by American Heart Association, Inc.