Abstract
Sustained pressure overload leads to compensatory myocardial hypertrophy and subsequent heart failure, a leading cause of morbidity and mortality. Further unraveling of the cellular processes involved is essential for development of new treatment strategies. We have investigated the hypothesis that the transmembrane Z-disc proteoglycan syndecan-4, a co-receptor for integrins, connecting extracellular matrix proteins to the cytoskeleton, is an important signal transducer in cardiomyocytes during development of concentric myocardial hypertrophy following pressure overload. Echocardiographic, histochemical and cardiomyocyte size measurements showed that syndecan-4−/− mice did not develop concentric myocardial hypertrophy as found in wild-type mice, but rather left ventricular dilatation and dysfunction following pressure overload. Protein and gene expression analyses revealed diminished activation of the central, pro-hypertrophic calcineurin-nuclear factor of activated T-cell (NFAT) signaling pathway. Cardiomyocytes from syndecan-4−/−-NFAT-luciferase reporter mice subjected to cyclic mechanical stretch, a hypertrophic stimulus, showed minimal activation of NFAT (1.6-fold) compared to 5.8-fold increase in NFAT-luciferase control cardiomyocytes. Accordingly, overexpression of syndecan-4 or introducing a cell-permeable membrane-targeted syndecan-4 polypeptide (gain of function) activated NFATc4 in vitro. Pull-down experiments demonstrated a direct intracellular syndecan-4-calcineurin interaction. This interaction and activation of NFAT were increased by dephosphorylation of serine 179 (pS179) in syndecan-4. During pressure overload, phosphorylation of syndecan-4 was decreased, and association between syndecan-4, calcineurin and its co-activator calmodulin increased. Moreover, calcineurin dephosphorylated pS179, indicating that calcineurin regulates its own binding and activation. Finally, patients with hypertrophic myocardium due to aortic stenosis had increased syndecan-4 levels with decreased pS179 which was associated with increased NFAT activation. In conclusion, our data show that syndecan-4 is essential for compensatory hypertrophy in the pressure overloaded heart. Specifically, syndecan-4 regulates stretch-induced activation of the calcineurin-NFAT pathway in cardiomyocytes. Thus, our data suggest that manipulation of syndecan-4 may provide an option for therapeutic modulation of calcineurin-NFAT signaling.
Highlights
Sustained pressure overload leads to compensatory myocardial hypertrophy and subsequent decompensation and heart failure, a leading cause of morbidity and mortality
Lack of syndecan-4 inhibits development of concentric myocardial hypertrophy during pressure overload Syndecan-42/2 mice had normal cardiac dimensions and function compared to wild-type (WT) mice (Table S1)
Three weeks after inducing pressure overload by aortic banding (AB), WT developed concentric left ventricular (LV) hypertrophy manifested as a significant increase in posterior wall thickness (Fig. 1A–C)
Summary
Sustained pressure overload leads to compensatory myocardial hypertrophy and subsequent decompensation and heart failure, a leading cause of morbidity and mortality. Mechanical stimuli, circulating hormones, as well as autocrine and paracrine factors are involved in initiating myocardial hypertrophy. Transduction of mechanical stimuli may involve molecules that bind the extracellular matrix to the cytoskeleton, but exactly which molecules participate is still unknown. Further unraveling of such signaling pathways is essential for defining novel therapeutic targets. Syndecan-4 is a transmembrane proteoglycan that connects extracellular matrix proteins to the cardiomyocyte cytoskeleton [2], and has been localized to costameres and Z-discs [3], potentially important sites for signal transduction across the membrane [4,5]. Syndecan-4 is a co-receptor for several growth factors [6]
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