Cardioprotective and anti‐atherosclerotic use of a biopolymer‐encapsulated glycosyltransferase inhibitor (607.9)

Although atherosclerosis and cardiac hypertrophy are synonymous with a western diet, very little is known about the effects of lowering glycosphingolipid load on interfering with such diet ‐induced phenotypes. Herein, we show that encapsulation of a glycosphingolipid glycosyltransferase inhibitor D‐threo‐1‐phenyl‐2 decanoylamino‐3‐morpholino‐1‐propanol(D‐PDMP) within a biopolymer markedly increased its efficacy in interfering with atherosclerosis and cardiac hypertrophy in Apo E ‐/‐ mice. Our imaging studies revealed that the residence time of 125I ‐tagged biopolymer encapsulated D‐PDMP in mice is ~24hrs compared with 1hr for native D‐PDMP. ApoE‐/‐ mice fed a western diet had markedly increased coronary artery atherosclerosis, aortic intima thickness (AoIMT ) and vascular stiffness. This was completely reversed by feeding mice 1mpk D‐PDMP encapsulated within the biopolymer (1BP) and this was comparable to mice fed 10mpk D‐PDMP alone. The activity of glycosyltransferases,,lipids and genes implicated in their regulation were markedly increased in apo‐/‐ mice fed western diet and this was interfered by treatment with 1BP. Intriguingly, western diet also caused extensive cardiac hypertrophy accompanied by a time ‐dependent decrease in fractional shortening and an increase in left ventricular mass. Accompanied with increased gene expression for atrial naturetic factor (ANP) and brain naturetic factor (BNP)‐established biomarkers of cardiac hypertrophy. Treatment with 1BP and or 10mpK D‐PDMP reversed cardiac hypertrophy biomarkers and cardiac function e.g. fractional shortening as well as left ventricular mass. Thus, encapsulation of D‐PDMP within a biopolymer is at least 10‐fold more efficacious in interfering/ameliorating atherosclerosis and cardiac hypertrophy in western diet fed apoE‐/‐ mice as compared to D ‐PDMP alone. Grant Funding Source : Supported by NHLBI grant P01HL107153.