Inhibiting glycosphingolipid glycosyltransferase activity prevents cardiac hypertrophy in apoE-/- mice fed a western diet

Background: Although diet enriched in high fat and cholesterol can induce cardiac hypertrophy, little is known about the role of glycosphigolipids and glycosyltransferases contributing to this phenotype. Herein, using transgenic apo E-/- mice fed a high fat and cholesterol diet we show that treatment with a glycosphingolipid inhibitor blunts cardiac hypertrophy. Methods and Results: Male apoE-/- mice were fed a western diet (20% fat and 1.25% cholesterol) from 12 weeks of age till 36 weeks with and without D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) daily by oral gavage (vehicle alone, 5 mpk and 10mpk) . At 12 week, 20 week and 36 week, trans -thoracic echocardiography were performed in conscious mice using an ultrasound system (n=5 in each group). Mice were euthanized once maladaptive cardiac hypertrophy time point is reach. Tissues such as the heart were harvested for were harvested for histochemical, biochemical, and molecular analysis to ascertain the effects of treatment on glycosphingolipid glycosyltransferase activity, gene/protein expression. We observed an age-dependent increase in the left ventricular mass (LVmass) and decline in fractional shortening indicative of cardiac hypertrophy and dysfunction which worsens with western diet. This was accompanied by increased gene expression for atrial natriuretic protein, Brain-type natriuretic protein, and increased protein expression of transforming growth factor, MAPK and AKT-1. Masson’s trichrome staining revealed hypertrophy in cardiomyocytes and extensive fibrosis. In contrast, treatment with D-PDMP preserved fractional shortening and the left ventricular mass to control levels over a 6 month treatment period. Also, the level of various cardiac glycosphingolipids and glycosyltransferases were decreased to control levels. Conclusion: Treatment with a glycosphingolipid glycosyltransferase inhibitor blunts cardiac hypertrophy in apoE-/- mice fed a western diet.