Reduced clusterin contents contribute to the pro-inflammatory and pro-senescent activity of low density lipoprotein particles in adiponectin deficient mice

Abstract

Purpose of the study Low adiponectin level is associated with highly oxidized low density lipoprotein (LDL) in patients with coronary heart disease. Clusterin inhibits LDL-induced monocyte chemotactic activity in artery wall. In the present study, we aim to investigate the relationship between adiponectin and clusterin in regulating the pathophysiological function of LDL. Methods Cholesterol and protein levels in LDL, HDL2 and HDL3 fractions were measured in serum from wild type and adiponectin-deficient mice after separation of these fractions by density gradient ultracentrifugation. Clusterin was detected in each lipoprotein fraction by Western blotting using specific antibody. LDL-induced endothelial cell senescence were determined by senescence-associated beta-galactosidase staining. Vascular functions were assessed in wild type and adiponectin-deficient mice using wire myography. Summary of the results Circulating levels of total, LDL- and HDL2-cholesterols were significantly increased in adiponectin-deficient mice by 64.7%, 32.5%, 36.1% compared with wild type control mice (All P < 0.05). Protein concentrations of these lipoprotein particles were similar between adiponectin-deficient and wild type mice. However, the clusterin levels were significantly decreased in LDL particles from adiponectin-deficient mice (fold change in protein expression: 0.2). Cellular senescence was significantly higher in primary porcine endothelial cells treated with the clusterin-poor LDL from adiponectin-deficient mice than that with the control LDL from wild type mice. In mice with dietary obesity, the endothelium-dependent contractions were significantly enhanced in arteries from the adiponectin-deficient mice compared to their wild type controls. Endothelium dependent relaxation were significantly attenuated by adiponectin deficiency. Conclusions Adiponectin exerts its anti-inflammatory and anti-atherogenic effects via regulating the function of LDL particles through its interactions with clusterin.