The heparan sulfate proteoglycan glypican-6 is upregulated in the failing heart, and regulates cardiomyocyte growth through ERK1/2 Signaling

Abstract

Pressure overload is a frequent cause of heart failure. Heart failure affects millions o patients worldwide and is a major cause of morbidity and mortality. Cell surface proteoglycan are emerging as molecular players in cardiac remodeling, and increased knowledg about their regulation and function is needed for improved understanding of cardiac pathogenesis Here we investigated glypicans (GPC1-6), a family of evolutionary conserve heparan sulfate proteoglycans anchored to the extracellular leaflet of the cell membrane, i experimental and clinical heart failure, and explored the function of glypican-6 in cardia cells in vitro. In mice subjected to pressure overload by aortic banding (AB), we observe elevated glypican-6 levels during hypertrophic remodeling and dilated, end-stage heart failure Consistently, glypican-6 mRNA was elevated in left ventricular myocardium fro explanted hearts of patients with end-stage, dilated heart failure with reduced ejection fraction Glypican-6 levels correlated negatively with left ventricular ejection fraction in patients and positively with lung weight after AB in mice. Glypican-6 mRNA was expressed in bot cardiac fibroblasts and cardiomyocytes, and the corresponding protein displayed differen sizes in the two cell types due to tissue-specific glycanation. Importantly, adenoviral overexpressio of glypican-6 in cultured cardiomyocytes increased protein synthesis an induced mRNA levels of the pro-hypertrophic signature gene ACTA1 and the hypertroph and heart failure signature genes encoding natriuretic peptides, NPPA and NPPB. Overexpressio of GPC6 induced ERK1/2 phosphorylation, and co-Treatment with the ERK inhibito U0126 attenuated the GPC6-induced increase in NPPA, NPPB and protein synthesis In conclusion, our data suggests that glypican-6 plays a role in clinical and experimenta heart failure progression by regulating cardiomyocyte growth through ERK signaling Copyright: