Abstract 789: Syndecan-4 is an Essential Signal Transducer for Activation of the Calcineurin-NFAT Pathway and Cardiac Hypertrophy in Mice
Background: We previously found all four syndecans upregulated following myocardial infarction (MI). Syndecan-4 is a co-receptor for growth factors and integrins, is localized to costameres and Z-disks, and may act as a mechanotransducer during development of cardiac hypertrophy.
Aim: To examine whether lack of syndecan-4 affects pathological hypertrophy and function during pressure overload and after MI.
Methods: Syndecan-4−/− mice were examined with echocardiography, left ventricular (LV) catheterization and electron microscopy, and compared to wild type mice (WT) before and after aortic banding (AB), coronary artery ligation or sham operation. The hypertrophic markers BNP and α-skeletal actin were measured by RT-qPCR, and intracellular signaling molecules were assessed by immunoblotting.
Results: Syndecan-4−/− mice showed no cardiac dysfunction at baseline. Electron microscopy showed irregular Z disc widening. Three weeks after AB, expression of α-skeletal actin in syndecan-4−/−mice (n=6) was only 28% of that in WT (n=6). Whereas WT (n=7) showed a 36% increase in posterior wall thickness with an associated decrease in LV diameter after AB, syndecan-4−/−mice (n=9) did not develop concentric hypertrophy. Instead, syndecan-4−/− mice showed signs of cardiac dysfunction with a significant increase in left atrial diameter and mitral flow deceleration. We found a specific inhibition of the calcineurin-NFAT pathway in syndecan-4−/−mice after AB with lower levels of NFAT available to the nucleus, expressed as total NFATc4 divided by phosphorylated NFATc4. No differences between the two genotypes were observed when examining phosphorylation of GSK3-β, p38, JNK, ERK1/2 and AKT, or translocation of PKC-α to the membrane. Following MI, BNP expression in syndecan-4−/− mice (n=6) was only 39% of that in WT (n=6). Most strikingly however, LV fractional shortening was significantly higher (15%) in syndecan-4−/− mice (n=9) compared to WT (10%, n=9), indicating beneficial effects of syndecan-4 deletion.
Conclusions: Lack of syndecan-4 inhibits development of concentric hypertrophy following pressure overload and attenuates development of heart failure following MI, probably due to specific inhibition of the calcineurin-NFAT pathway.