Antioxidative and Antiatherosclerotic Effects of Human Apolipoprotein A-IV in Apolipoprotein E–Deficient Mice

Abstract

Abstract-Mice expressing human apolipoprotein A-IV (apoA-IV) mainly in the intestine were obtained in an apolipoprotein E-deficient (apoE 0 ) background (apoA-IV/E 0 mice). Quantification of aortic lesions and plasma lipid determination showed that compared with their control apoE 0 counterparts, the apoA-IV/E 0 mice are protected against atherosclerosis without an increase in HDL cholesterol. Because oxidized lipoproteins play an important role in atherogenesis, we tested whether the protection observed in these animals is accompanied by an in vivo reduction of the oxidation parameters. The lag time in the formation of conjugated dienes during copper-mediated oxidation, the aggregation state of LDL, and the presence of anti-oxidized LDL antibodies were measured. The presence of oxidized proteins in tissues and the presence of oxidation-specific epitopes in heart sections of atherosclerotic lesions were also analyzed. Except for lag time, the results showed that the oxidation parameters were reduced in the apoA-IV/E 0 mice compared with the apoE 0 mice. This suggests that human apoA-IV acts in vivo as an antioxidant. In addition, human apoA-IV accumulation was detected in the atherosclerotic lesions of apoA-IV/E 0 mice, suggesting that apoA-IV may inhibit oxidative damage to local tissues, thus decreasing the progression of atherosclerosis. (Arterioscler Thromb Vasc

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

“…We cannot at this point determine: a) whether the increased risk associated with S347 homozygosity is a result of inherent lower apoA-IV levels and therefore lower antioxidant potential; b) whether the apoA-IV S347 protein itself has poorer antioxidant activity compared with apoA-IV T347, and therefore S347 homozygotes have lower antioxidant potential; or c) whether, by accelerating postprandial lipid clearance, the S347 variant causes changes in lipid metabolism (e.g., increased hepatic oxidation of dietary polyunsaturated fats) that are themselves associated with an increased oxidation status. APOA4/Apoe Ϫ/Ϫ mice were found to be protected against atherosclerosis, without an increase in HDL concentration, and displayed reduced oxidative markers, including aldehyde-modified LDL (16). ApoA-IV was found to have accumulated in the damaged arterial wall of these animals and thus could be acting as an antioxidant in situ (16).…”

“…APOA4/Apoe Ϫ/Ϫ mice were found to be protected against atherosclerosis, without an increase in HDL concentration, and displayed reduced oxidative markers, including aldehyde-modified LDL (16). ApoA-IV was found to have accumulated in the damaged arterial wall of these animals and thus could be acting as an antioxidant in situ (16). Inhibition of Cu 2ϩ -induced lipoprotein oxidation by human apoA-IV results in reduced tryptophan fluorescence, suggesting the prevention of Cu 2ϩ binding to lipoprotein particles and causing lipid peroxidation, implying a chelating role of apoA-IV in preventing lipid peroxidation (35).…”

The apolipoprotein A-IV Gln360His polymorphism predicts progression of coronary artery calcification in patients with type 1 diabetes

“…We can only speculate as to whether the pro-atherogenic effect of the APOA4 His360 allele in type 1 diabetic subjects is dependent on defective antioxidant properties of the APOA4-2 isoform [17,22]. In this case, the diminished protective role of APOA4 could be more pronounced in situations when production of reactive oxygen species is increased (such as with poorly controlled diabetes), while in subjects with relatively lower oxidative stress, the significance of this genetic variant in rapid progression of atherosclerosis is less important [31,43].…”

“…APOA4 plays an important role in reverse cholesterol transport from peripheral cells to the liver by promoting cholesterol efflux from cells (including macrophages) [19] and by enhancing formation of HDL via activation of lecithin-cholesterol acyl transferase [20]. APOA4 can modulate the transfer of cholesteryl esters from HDL to LDL [21], influence activation of lipoprotein lipase, and serve as a naturally occurring potent anti-oxidant [22]. Low plasma APOA4 levels have previously been associated with an increased risk of CAD [18,23].…”

Improving the diffraction of apoA-IV crystals through extreme dehydration

“…As a prominent component of high-density lipoproteins (HDL), apoA-IV has been proposed to participate in the removal of excess cholesterol from peripheral cells, such as those in the coronary artery wall, and to return it to the liver for catabolism. ApoA-IV has also been proposed to function as an antioxidant (Qin et al, 1998;Ostos et al, 2001), a satiety factor (Tso & Xu, 2003) and a mediator of gut inflammation (Vowinkel et al, 2004), and has recently been linked to -amyloid clearance in the brain (Cui et al, 2011).…”