A combinational therapy on atherosclerosis

Abstract

LXR, a ligand‐activated transcription factor, plays a central role in cholesterol and fatty acid biosynthesis/metabolism. LXR activation induces macrophage ABCA1 expression, a molecule facilitating cholesterol efflux and inhibiting formation of macrophage/foam cells and development of atherosclerosis. LXR ligands inhibit atherosclerosis but induce severe hypertriglyceridemia. Our previous report demonstrates that ERK1/2 inhibitors synergize LXR ligand‐induced macrophage ABCA1 expression and cholesterol efflux (JBC 2010;285:6316–6326) indicating the application of LXR ligands plus ERK1/2 inhibitors on atherosclerosis. We herein report that the combination of an LXR ligand (T09013170) and an ERK1/2 inhibitor (U0126) both at low doses inhibited atherosclerosis in apoE−/− mice. More importantly, the T0901317‐induced hypertriglyceridemia was blocked by U0126. The mechanism study indicated that the combinational therapy had a little effect on fatty acid biosynthesis but greatly promoted expression of genes responsive for triglycerides metabolism. Furthermore, we investigated the effect of the combinational therapy on regression of atherosclerosis. Our results indicated the combinational therapy had little effect on lesion development in mice with advanced lesions and continued on a high‐fat diet. However, a regression of lesion development was observed in the mice receiving the combinational therapy while returning to normal chow from the high‐fat diet. Taken together, our study suggests that the combinational of LXR ligands and ERK1/2 inhibitors can be a novel therapy to inhibit and regress atherosclerosis without adverse effects.