Human Apolipoprotein A-IV Reduces Secretion of Proinflammatory Cytokines and Atherosclerotic Effects of a Chronic Infection Mimicked by Lipopolysaccharide

Abstract

Objective— Expression of human apolipoprotein (h-apo) A-IV in apoE-deficient (apoE 0 ) mice (h-apoA-IV/E 0 ) reduces susceptibility to atherosclerosis. Chronic infection mimicked by exposure to lipopolysaccharide (LPS) increases the size of atherosclerosis lesions in apoE 0 mice. Thus, we used h-apoA-IV/E 0 mice to determine whether h-apoA-IV plays a protective role after LPS administration. Methods and Results— We injected apoE 0 , h-apoA-IV/E 0 , and C57Bl/6 (wild-type) mice intraperitoneally with either LPS or phosphate-buffered saline (PBS) every week for 10 weeks. Atherosclerotic lesions were significantly smaller in h-apoA-IV/E 0 mice treated with LPS than in their apoE 0 counterparts. The titers of IgG2a and IgG2b autoantibodies to oxidized low-density lipoprotein (LDL) were higher in the LPS-group of h-apoA-IV/E 0 mice than in apoE 0 mice, suggesting that the Th1 response is stronger in the presence of h-apoA-IV. Lymphocytes from the blood, liver, spleen, and thymus of h-apoA-IV/E 0 mice treated with LPS produced less IL-4, INF-γ, and TNF-α proinflammatory cytokines than their apoE 0 counterparts. Furthermore, we demonstrated that recombinant h-apoA-IV blocks the LPS-induced stimulation of monocytes. Conclusions— The expression of h-apoA-IV in apoE 0 mice reduces the susceptibility to atherogenesis and decreases the secretion of proinflammatory cytokines after LPS administration.

High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease

“…It has also been reported that HDL-associated apoJ can inhibit LDL oxidation by artery wall cells ( 64 ). In addition, apoA-IV has been demonstrated to exert anti-oxidant, anti-infl ammatory, and anti-atherosclerotic actions in vivo (65)(66)(67).…”

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

“…In contrast, apoE4 has been suggested to be proinflammatory (Ophir et al 2005). Another HDL-associated protein, apoA-IV, showed anti-atherosclerotic, antiinflammatory, and antioxidant actions in vivo (Ostos et al 2001;Recalde et al 2004;Vowinkel et al 2004). In addition, apoJ, also called clusterin, has been reported to block LDL oxidation by artery wall cells (Navab et al 1997).…”

The APOA4 T347S variant is associated with reduced plasma TAOS in subjects with diabetes mellitus and cardiovascular disease

“…LPS mimics chronic infection and increases the atherosclerotic lesion in Apoe -deficient mice. However, in APOA4/Apoe Ϫ / Ϫ mice, lesion size was reduced and proinflammatory cytokine production was lower, although autoantibodies to oxidized LDL (OX-LDL) were higher (17). These studies provide additional insight into the anti-inflammatory, antiatherogenic role of apoA-IV.…”

“…Further, these mice had reduced oxidative markers, including aldehyde-modified LDL, suggesting an antioxidant effect of apoA-IV (16), although this, per se, does not prove that the antiatherogenic effect of apoA-IV is a result of antioxidant potential. More recently, the protective effect of the human APOA4 transgene in APOA4/ Apoe Ϫ / Ϫ mice was examined in relation to lipopolysaccharide (LPS) exposure (17). LPS mimics chronic infection and increases the atherosclerotic lesion in Apoe -deficient mice.…”