National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
J Lipid Res. 2010 Dec;51(12):3434-42. doi: 10.1194/jlr.M008573. Epub 2010 Sep 3.
The previous studies in our laboratory revealed that seven cysteine mutants of apolipoprotein A-I (apoA-I) have different structural features and biological activities in vitro and in vivo. To investigate the potential cardioprotective effects of apolipoprotein A-I(N74C) [apoA-I(N74C)], we examined the anti-inflammatory, antioxidant, and antiatherosclerotic effects of this cysteine mutant in a rapid atherosclerosis model induced by perivascular carotid collar placement in apoE⁻/⁻ mice. Lipid-free apoA-I(N74C) showed a significant increased antioxidant potency in low density lipoprotein (LDL) oxidation in vitro and reduced intracellular lipid accumulation in THP-1-derived macrophages, relative to wild-type apoA-I (apoA-Iwt). Mice injected with recombinant HDL (rHDL) reconstituted with apoA-I(N74C) (named rHDL74) through tail veins (40 mg/kg of body weight, three injections) had a significant lower level of serum interleukin-6 (IL-6) and enhanced serum antioxidation compared with mice receiving rHDL reconstituted with apoA-Iwt (named rHDLwt). Moreover, compared with rHDLwt, the rHDL74 in vivo injection resulted in a significant decrease in plaque size, ratio of aorta intima to media, arterial remodeling, and macrophage content in lesions. In summary, intravenous injection with rHDL74 reconstituted with apoA-I cysteine mutant apoA-I (N74C) dramatically delays the development of atherosclerosis induced by perivascular carotid collar placement and reduces vascular remodeling in the carotid artery in apoE⁻/⁻ mice.
先前我们实验室的研究表明，载脂蛋白 A-I（apoA-I）的 7 个半胱氨酸突变体在体外和体内具有不同的结构特征和生物学活性。为了研究载脂蛋白 A-I（N74C）[apoA-I（N74C）]的潜在心脏保护作用，我们在载脂蛋白 E 基因敲除（apoE-/-）小鼠的血管周围颈动脉套环放置诱导的快速动脉粥样硬化模型中，研究了这种半胱氨酸突变体的抗炎、抗氧化和抗动脉粥样硬化作用。与野生型载脂蛋白 A-I（apoA-Iwt）相比，无脂载脂蛋白 A-I（N74C）在体外低密度脂蛋白（LDL）氧化中表现出显著增强的抗氧化能力，并且减少了 THP-1 衍生巨噬细胞中的细胞内脂质积累。通过尾静脉（40mg/kg 体重，3 次注射）注射重组高密度脂蛋白（rHDL）与载脂蛋白 A-I（N74C）（命名为 rHDL74）的小鼠，与接受载脂蛋白 A-Iwt 重建的 rHDL（命名为 rHDLwt）的小鼠相比，血清白细胞介素 6（IL-6）水平显著降低，血清抗氧化能力增强。此外，与 rHDLwt 相比，rHDL74 的体内注射导致斑块大小、主动脉内膜与中膜的比值、动脉重塑和病变中巨噬细胞含量显著减少。总之，静脉注射载脂蛋白 A-I 半胱氨酸突变体载脂蛋白 A-I（N74C）重建的 rHDL74 可显著延迟血管周围颈动脉套环放置诱导的动脉粥样硬化的发展，并减少 apoE-/-小鼠颈动脉中的血管重塑。
