Abstract 261: Inhibitory Effect of Isosorbide Mononitrate on the Formation of Atherosclerosis in Low-Density Lipoprotein Receptor and Heme Oxygenase-2 Double Knockout Mice

Abstract

Objective: Isosorbide mononitrate (ISMN), a well-known nitrate, have been widely used in the management of ischemic heart disease. Although it significantly alleviate angina pain, development of tolerance and its pro-oxidant properties have been provoking continuing debate. To this day, the effect of nitrate therapy on atherosclerotic formation remains unsolved. To elucidate this clinically-important problem, we examined the effect of ISMN treatment on the atherosclerotic formation using high-fat fed low density lipoprotein (LDL) receptor and heme oxygenase-2 double-deficient (LDL-R/HO-2 -/-) mice, in which only anti-oxidative and anti-inflammatory isoform of heme oxygenase-1 (HO-1) had been expressed in atherosclerotic arterial wall cells. We also examined the role of bilirubin, a product of HO-1 reaction, in these ISMN models. Methods: During 6 week high-fat diet, LDL-R/HO-2 -/- mice were treated with ISMN (2 mg/kg/day or 200 mg/kg/day). Control animals were treated with vehicle. After sacrifice, resultant atherosclerotic formation was determined. We also examined the expressions of anti-oxidative enzyme such as HO-1 and extracellular superoxide dismutase (ecSOD), changes of reactive oxidative metabolites (d-ROM) in plasma. We also examined the effects of ISMN on bilirubin formation using cultured endothelial cells. Results: ISMN treatments did not alter plasma lipid profiles. ISMN treatment (200 mg/kg/day) significantly inhibited atherosclerotic lesion formation with marked HO-1 induction in aortic wall. In contrast, we did not observe the changes of extracellular superoxide dismutase (ecSOD) expression. ISMN treatments did not increase the levels of plasma d-ROM. However, ISMN treatments significantly increased bilirubin production in cultured endothelial cells. Conclusions: These results suggest that optimal ISMN treatment significantly inhibit atherosclerotic lesion formation via HO-1 induction although the role of bilirubin in these models needs to be further elucidated.