Objective Apolipoprotein A-II (apo A-II) is the second major apolipoprotein of HDLs, yet its pathophysiological roles in the development of atherosclerosis remain unknown. We aimed to examine whether apo A-II plays any role in atherogenesis and if so, to elucidate the mechanism involved. Methods and Results We compared the susceptibility of human apo A-II transgenic (Tg) rabbits to cholesterol diet-induced atherosclerosis with non-Tg littermate rabbits. Tg rabbits developed significantly less aortic and coronary atherosclerosis than their non-Tg littermates while total plasma cholesterol levels were similar. Atherosclerotic lesions of Tg rabbits were characterized by reduced macrophages and smooth muscle cells and apo A-II immunoreactive proteins were frequently detected in the lesions. Tg rabbits exhibited low levels of plasma CRP and blood leukocytes compared to non-Tg rabbits and HDLs of Tg rabbit plasma exerted stronger cholesterol efflux activity and inhibitory effects on the inflammatory cytokine expression by macrophages in vitro than HDLs isolated from non-Tg rabbits. In addition, β-VLDLs of Tg rabbits were less sensitive to copper-induced oxidation than β-VLDLs of non-Tg rabbits. Conclusions These results suggest that enrichment of apo A-II in HDL particles has atheroprotective effects and apo A-II may become a target for the treatment of atherosclerosis.

Objective-Apolipoprotein AII (apoAII) is the second major apolipoprotein in high-density lipoprotein (HDL). However, the physiological functions of apoAII in lipoprotein metabolism have not been fully elucidated. Methods and Results-We generated human apoAII transgenic (Tg) rabbits, a species that normally does not have an endogenous apoAII gene. Plasma levels of human apoAII in Tg rabbits were Ϸ30 mg/dL, similar to the plasma levels in healthy humans. The expression of human apoAII in Tg rabbits resulted in increased levels of plasma triglycerides, total cholesterol, and phospholipids accompanied by a marked reduction in HDL-cholesterol levels compared with non-Tg littermates. Analysis of lipoprotein fractions showed that hyperlipidemia exhibited by Tg rabbits was caused by elevated levels of very-low-density lipoproteins ( Key Words: apolipoprotein Ⅲ lipase Ⅲ transgenic rabbits Ⅲ hyperlipidemia Ⅲ HDL H igh levels of plasma high-density lipoproteins (HDL) are associated with a low incidence of cardiovascular disease. 1 HDL contains 2 major apolipoproteins (apo): apoAI and apoAII. It is generally accepted that apoAI plays a central role in reverse cholesterol transport and protects against atherosclerosis 2,3 ; however, apoAII functions have not been clearly characterized. 4 -6 See accompanying article on page 1984Clinical and epidemiological studies have yielded conflicting results regarding the relationship between plasma apoAII levels and coronary heart disease: apoAII is either proatherogenic 7 or atheroprotective. 8 The Ϫ265C polymorphism in the apoAII promoter region was shown to be associated with decreased plasma apoAII concentration and enhance postprandial metabolism of large very-low-density lipoproteins (VLDL). 9 Nevertheless, apoAII has long been considered to be of physiologically minor importance in lipoprotein metabolism because apoAII deficiency is not associated with a high susceptibility to coronary heart disease. 10 ApoAII transgenic (Tg) mice along with knock-out (KO) mice have revealed multiple functions of apoAII. 4,5 Both human and mouse apoAII in Tg mice are involved in VLDL metabolism, but mouse apoAII is also associated with obesity and insulin resistance. [11][12][13] In addition, mouse apoAII is proatherogenic in chow-fed Tg mice, whereas human apoAII is either atheroprotective or proatherogenic in Tg mice dependent on an atherogenic diet. 14 -17 Although the cause of these discrepancies in different mice expressing different transgenes is unclear, it seems that there is a species difference in apoAII functions between human and mouse, and that the precise physiological functions of apoAII in vivo remain to be elucidated. Studies using Tg mice are often complicated by additional factors such as the effect of human homodimer apoAII versus murine monomer apoAII, transgenic apoAII (either human or murine) versus endogenous murine apoAII,