Inhibition of ERK1/2 and activation of LXR synergistically reduce atherosclerotic lesions in ApoE-deficient mice.

Abstract

OBJECTIVE:

Activation of liver X receptor (LXR) inhibits atherosclerosis but induces hypertriglyceridemia. In vitro, it has been shown that mitogen-activated protein kinase kinase 1/2 (MEK1/2) inhibitor synergizes LXR ligand-induced macrophage ABCA1 expression and cholesterol efflux. In this study, we determined whether MEK1/2 (U0126) and LXR ligand (T0901317) can have a synergistic effect on the reduction of atherosclerosis while eliminating LXR ligand-induced fatty livers and hypertriglyceridemia. We also set out to identify the cellular mechanisms of the actions.

APPROACH AND RESULTS:

Wild-type mice were used to determine the effect of U0126 on a high-fat diet or high-fat diet plus T0901317-induced transient dyslipidemia and liver injury. ApoE deficient (apoE(-/-)) mice or mice with advanced lesions were used to determine the effect of the combination of T0901317 and U0126 on atherosclerosis and hypertriglyceridemia. We found that U0126 protected animals against T0901317-induced transient or long-term hepatic lipid accumulation, liver injury, and hypertriglyceridemia. Meanwhile, the combination of T0901317 and U0126 inhibited the development of atherosclerosis in a synergistic manner and reduced advanced lesions. Mechanistically, in addition to synergistic induction of macrophage ABCA1 expression, the combination of U0126 and T0901317 maintained arterial wall integrity, inhibited macrophage accumulation in aortas and formation of macrophages/foam cells, and activated reverse cholesterol transport. The inhibition of T0901317-induced lipid accumulation by the combined U0126 might be attributed to inactivation of lipogenesis and activation of lipolysis/fatty acid oxidation pathways.

CONCLUSIONS:

Our study suggests that the combination of mitogen-activated protein kinase kinase 1/2 inhibitor and LXR ligand can function as a novel therapy to synergistically reduce atherosclerosis while eliminating LXR-induced deleterious effects.

• Authors: Yuanli Chen, Yajun Duan, Xiaoxiao Yang, Lei Sun, Mengyang Liu, Qixue Wang, Xingzhe Ma, Wenwen Zhang, Xiaoju Li, Wenquan Hu, Robert Q Miao, Rong Xiang, David P Hajjar, Jihong Han
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 4 Pg. 948-59 (Apr 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 25810299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Apolipoproteins E
• Butadienes
• Hydrocarbons, Fluorinated
• Liver X Receptors
• Nitriles
• Orphan Nuclear Receptors
• Protein Kinase Inhibitors
• Sulfonamides
• T0901317
• U 0126
• Cholesterol
• Mapk1 protein, mouse
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Animals
• Aorta (drug effects, enzymology, pathology)
• Aortic Diseases (enzymology, genetics, pathology, prevention & control)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (enzymology, genetics, pathology, prevention & control)
• Butadienes (pharmacology)
• Chemical and Drug Induced Liver Injury (enzymology, pathology, prevention & control)
• Cholesterol (metabolism)
• Disease Models, Animal
• Drug Synergism
• Drug Therapy, Combination
• Fatty Liver (chemically induced, enzymology, pathology, prevention & control)
• Female
• Foam Cells (drug effects, enzymology, pathology)
• Hep G2 Cells
• Humans
• Hydrocarbons, Fluorinated (pharmacology, toxicity)
• Hypertriglyceridemia (chemically induced, enzymology, pathology, prevention & control)
• Liver (drug effects, metabolism)
• Liver X Receptors
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Mitogen-Activated Protein Kinase 1 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 3 (antagonists & inhibitors, metabolism)
• Nitriles (pharmacology)
• Orphan Nuclear Receptors (agonists, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology, toxicity)