On the road to discovering a new actor of cardiac pathological hypertrophy

Abstract

Cardiac hypertrophy develops in response to hemodynamic overload, which can occur in hypertension and aortic stenosis. Maintenance of these pathological conditions eventually evolves into heart failure (HF) and death. O-GlcNAcylation, a post-translational modification of proteins, has been shown to drastically increase during cardiac hypertrophy development and to mediate maladaptive remodeling implicated in the progression of HF. Using mass spectrometry analysis, our lab recently identified several O-GlcNAcylated cardiac proteins that could be involved in such remodeling. Among them, O-GlcNAcylated protein 1 (OGP-1) looks to be a promising candidate. We investigated the role of OGP-1 in cardiac hypertrophy development. Change in OGP-1 expression was followed in neonatal rat cardiomyocytes (NRVM) treated with the pro-hypertrophic agent phenylephrine (PE) for 24 h. The same was done in vivo in two different hypertrophic mouse models, the first induced by Angiotensin II (Ang II) infusion for 5 to 14 days and the second promoted by transverse aortic constriction (TAC) for 2 to 6 weeks. The expression of OGP-1 was also evaluated in human hearts biopsies from different degree of cardiac remodeling. NRVM size was evaluated using α-actinin staining that labels sarcomeric Z-line. Pro-hypertrophic markers (ANP, BNP and β-MHC) were analyzed by quantitative PCR. The effect of OGP-1 overexpression and siRNA-mediated silencing was finally performed in NRVM. A significant decrease in OGP-1 expression was detected in both in vitro and in vivo rodent hypertrophic models. To evaluate the putative implication of OGP-1 in the regulation of cardiac hypertrophy, we repressed OGP-1 expression using siRNA in NRVM. We showed that OGP-1 knockdown induced a basal increase in cell size, similar to that found in PE-treated control cardiomyocytes, suggesting that OGP-1 repression may be sufficient to induce cardiomyocyte hypertrophy. Unexpectedly, the increase in cell size was not related to classical pro-hypertrophic pathways, ANP, BNP and β-MHC expression being unaffected. The other way round, OGP-1 overexpression prevented PE-induced NRVM hypertrophy. Our results underlie OGP-1 as a potential anti-hypertrophic protein and an interesting future target for the treatment of cardiac hypertrophy. Further investigations aim to identify the precise function of OGP-1 in the regulation of cardiac hypertrophy.