Intermedin1-53 Improves Atherosclerosis by Reducing Local Endothelial Damage via AMPK Signaling Pathway in Obese apoE-Deficient Mice.

Abstract

Background: Atherosclerotic cardiovascular diseases (CVD) are commonly found in obesity. Endothelial inflammation accompanied by oxidative stress is a crucial risk factor and a key initiating step for the pathogenesis of atherosclerosis (AS). In the present study, the role and mechanism of intermedin (IMD), a potent active peptide, in endothelial damage in AS in obese apolipoprotein E-deficient (apoE^-/-) mice were investigated.

Methods and results: In vivo, IMD_1-53 was infused via Alzet mini-osmotic pump in apoE^-/- mice with high-fat diet (HFD) for 4 weeks. In vitro, palmitic acid (PA) and oxidized low density lipoprotein (Ox-LDL) were used to stimulate human umbilical vein endothelial cells (HUVECs) for exploring the potential mechanism of IMD_1-53 action on endothelial damage. We found that IMD_1-53 application remarkably improved plasma lipid profiles, hepatic lipid accumulation and its cholesterol levels, and vascular lipid accumulation and lesion sizes. Moreover, IMD_1-53 markedly increased eNOS expression and decreased the levels of vascular inflammatory factors and ROS. In vitro, the combination of PA and Ox-LDL caused more severe inflammatory and oxidative damages and lower expression of eNOS, which were significantly inhibited by IMD_1-53. IMD_1-53 notably induced AMPK phosphorylation, and the inhibition of AMPK activation markedly reversed the anti-inflammatory and antioxidant effects of IMD_1-53 on PA and Ox-LDL-treated HUVECs.

Conclusion: IMD_1-53 improves AS partially by reducing endothelial inflammatory and oxidative damage via AMPK signaling pathway and decreasing vascular lipid accumulation involving the improvement of lipid profiles in blood and in liver in a state of obesity.