The Sialyltransferase, ST3Gal4, Protects Against Pressure‐Induced Cardiac Hypertrophy

Abstract

There are more than 40 types of human congenital disorders of glycosylation (CDG) characterized by a relatively modest but variable reduction in glycoprotein glycosylation that leads to dramatic multi‐system effects, including cardiac dysfunction. Nearly all CDG patients suffer from reduced protein sialylation. We sought to question whether and how reduced sialylation contributes to the observed cardiac symptoms that include dilated or hypertrophic cardiomyopathies. Trans‐aortic constriction (TAC) of a sialyltransferase knockout strain, ST3Gal4, that produces glycoproteins with fewer sialic acids attached was used to question whether ST3Gal4 expression protected against heart failure. Post‐TAC hypertrophy was observed in all mice, but survival and cardiac function of the post‐TAC ST3Gal4−/− mice were significantly compromised compared to wild type (WT) animals. Survival at one week post‐TAC was ~50% of WT (WT, 74%; ST3Gal4−/−, 38%), with ejection fraction (EF) and fraction shortening (FS) severely reduced (WT to ST3Gal4−/− in %: EF, 54 ± 2 to 29 ± 4; FS, 28 ± 1 to 14 ± 2), and ventricles and myocytes were significantly larger than WT. The calcineurin signaling pathway was upregulated in the ST3Gal4−/− ventricle. Together, the data suggest that ST3Gal4 gene deletion results in reduced protection against pressure‐induced hypertrophy and heart failure, likely through increased calcineurin activity.