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Abstract
Pressure overload is a frequent cause of heart failure. Heart failure affects millions of patients worldwide and is a major cause of morbidity and mortality. Cell surface proteoglycans are emerging as molecular players in cardiac remodeling, and increased knowledge about their regulation and function is needed for improved understanding of cardiac pathogenesis. Here we investigated glypicans (GPC1-6), a family of evolutionary conserved heparan sulfate proteoglycans anchored to the extracellular leaflet of the cell membrane, in experimental and clinical heart failure, and explored the function of glypican-6 in cardiac cells in vitro. In mice subjected to pressure overload by aortic banding (AB), we observed elevated glypican-6 levels during hypertrophic remodeling and dilated, end-stage heart failure. Consistently, glypican-6 mRNA was elevated in left ventricular myocardium from 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 both cardiac fibroblasts and cardiomyocytes, and the corresponding protein displayed different sizes in the two cell types due to tissue-specific glycanation. Importantly, adenoviral overexpression of glypican-6 in cultured cardiomyocytes increased protein synthesis and induced mRNA levels of the pro-hypertrophic signature gene ACTA1 and the hypertrophy and heart failure signature genes encoding natriuretic peptides, NPPA and NPPB. Overexpression of GPC6 induced ERK1/2 phosphorylation, and co-treatment with the ERK inhibitor 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 experimental heart failure progression by regulating cardiomyocyte growth through ERK signaling.
Highlights
Heart failure is a syndrome affecting millions of people worldwide and is currently one of the main causes of morbidity and mortality, carrying huge monetary costs for society [1]
To investigate whether glypican expression was regulated in the failing heart, we measured cardiac GPC1-6 transcript levels in mice subjected to pressure overload induced by aortic banding (AB) (Fig 1A and Table 1)
We examined the cardiac phenotype after AB by echocardiography, and harvested left ventricle (LV) during the acute phase (i.e. 24 h post-AB), during hypertrophic remodeling (1 and 3 weeks post-AB) and during end-stage, dilated heart failure (16 and 18 weeks post-AB)
Summary
Heart failure is a syndrome affecting millions of people worldwide and is currently one of the main causes of morbidity and mortality, carrying huge monetary costs for society [1]. Cardiac remodeling encompasses cellular and extracellular matrix alterations in the heart, including cardiomyocyte hypertrophy and apoptosis, and fibrosis [3]. We and others have established that proteoglycans, proteins substituted with glycosaminoglycans (GAG) chains, play important roles during cardiac remodeling and failure. Syndecan-4 regulates aspects of fibrosis, inflammation and cardiomyocyte hypertrophy in response to pressure overload [5,6,7,8,9]. Syndecans (SDC1-4) and glypicans (GPC1-6) are cell surface proteoglycans and the main sources of cell surface heparan sulfate (HS) GAGs [10, 11]. Glypicans are expressed in the heart [12, 13], their roles in cardiac remodeling and failure are unknown
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