Virginia Commonwealth大学的科学家最近确定了一种重要的酶——CEH（cholesteryl ester hydrolase）在降低心脏病风险方面的作用。这为发展新的减少血管粥样沉积和帮助预测病人患心脏病可能性带来了希望。新方法除了像现有方法一样能防止新血管粥样斑块形成外，还可以减少已经存在的斑块。
心脏病产生原因在于负责向心脏供血的冠状动脉中粥样斑块形成，当血液中的单核细胞进入血管壁，并且消耗大量的坏胆固醇－LDL后就会形成粥样沉积。而对这些泡沫状细胞而言唯一的处理胆固醇的方法依赖于HDL——好胆固醇。泡沫状细胞中的CEH酶负责调节能被HDL去除的胆固醇含量。
在VCU医学院内科医学副教授Shobha Ghosh领导的研究中，小组首次发现动脉壁中的细胞如何使胆固醇变得能被HDL去除。利用高脂肪和胆固醇食物喂养的转基因老鼠，小组证实含有人类CEH基因的老鼠能通过去除血管凝集的泡沫状细胞中胆固醇来大大降低心脏病风险。
Ghosh说：“目前治疗心脏病的重点在于减少循环系统中的LDL。而我们的研究证明如果能增加粥样斑块中胆固醇的去除量，那么即使不改变LDL浓度粥样斑块也会大大减少。这些发现不但改变了目前对心脏病治疗的想法，通过将CEH作为治疗目标，未来心脏病人能得到更好的治疗手段。除此之外，利用人类血液细胞中CEH浓度，我们希望能预测心脏病发生几率。”
Ghosh表示，小组研究重点在于泡沫状巨噬细胞，这是储存大量胆固醇并导致动脉粥样沉积和阻塞的原因。以上结果发表在10月份的《临床检查杂志》（The Journal of Clinical Investigation）上。（教育部科技发展中心）
原始出处:
J. Clin. Invest. 117:2983-2992 (2007). doi:10.1172/JCI30485
Macrophage-specific transgenic expression of cholesteryl ester hydrolase significantly reduces atherosclerosis and lesion necrosis in Ldlr–/– mice
Bin Zhao1, Jingmei Song1, Woon N. Chow2, Richard W. St. Clair3, Lawrence L. Rudel3 and Shobha Ghosh1
1Department of Internal Medicine and 2Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia, USA. 3Department of Pathology, Lipid Sciences Section, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Address correspondence to: Shobha Ghosh, Department of Internal Medicine, Division of Pulmonary and Critical Care, Virginia Commonwealth University, Room 8-047, Sanger Hall, 1101 E. Marshall Street, Richmond, Virginia 23298-0050, USA. Phone: (804) 827-1012; Fax: (804) 827-1782; E-mail: Shobha@vcu.edu .
Received for publication September 27, 2006, and accepted in revised form June 26, 2007.Accumulation of cholesteryl esters (CEs) in macrophage foam cells, central to atherosclerotic plaque formation, occurs as a result of imbalance between the cholesterol influx and efflux pathways. While the uptake, or influx, of modified lipoproteins is largely unregulated, extracellular acceptor-mediated free cholesterol (FC) efflux is rate limited by the intracellular hydrolysis of CE. We previously identified and cloned a neutral CE hydrolase (CEH) from human macrophages and demonstrated its role in cellular CE mobilization. In the present study, we examined the hypothesis that macrophage-specific overexpression of CEH in atherosclerosis-susceptible Ldlr–/– mice will result in reduction of diet-induced atherosclerosis. Transgenic mice overexpressing this CEH specifically in the macrophages (driven by scavenger receptor promoter/enhancer) were developed and crossed into the Ldlr–/– background (Ldlr–/–CEHTg mice). Macrophage-specific overexpression of CEH led to a significant reduction in the lesion area and cholesterol content of high-fat, high-cholesterol diet–induced atherosclerotic lesions. The lesions from Ldlr–/–CEHTg mice did not have increased FC, were less necrotic, and contained significantly higher numbers of viable macrophage foam cells. Higher CEH-mediated FC efflux resulted in enhanced flux of FC from macrophages to gall bladder bile and feces in vivo. These studies demonstrate that by enhancing cholesterol efflux and reverse cholesterol transport, macrophage-specific overexpression of CEH is antiatherogenic.
