Virginia Commonwealth大學(xué)的科學(xué)家最近確定了一種重要的酶——CEH（cholesteryl ester hydrolase）在降低心臟病風(fēng)險(xiǎn)方面的作用,。這為發(fā)展新的減少血管粥樣沉積和幫助預(yù)測(cè)病人患心臟病可能性帶來(lái)了希望。新方法除了像現(xiàn)有方法一樣能防止新血管粥樣斑塊形成外,，還可以減少已經(jīng)存在的斑塊,。
心臟病產(chǎn)生原因在于負(fù)責(zé)向心臟供血的冠狀動(dòng)脈中粥樣斑塊形成,，當(dāng)血液中的單核細(xì)胞進(jìn)入血管壁,，并且消耗大量的壞膽固醇－LDL后就會(huì)形成粥樣沉積。而對(duì)這些泡沫狀細(xì)胞而言唯一的處理膽固醇的方法依賴于HDL——好膽固醇,。泡沫狀細(xì)胞中的CEH酶負(fù)責(zé)調(diào)節(jié)能被HDL去除的膽固醇含量,。
在VCU醫(yī)學(xué)院內(nèi)科醫(yī)學(xué)副教授Shobha Ghosh領(lǐng)導(dǎo)的研究中，小組首次發(fā)現(xiàn)動(dòng)脈壁中的細(xì)胞如何使膽固醇變得能被HDL去除,。利用高脂肪和膽固醇食物喂養(yǎng)的轉(zhuǎn)基因老鼠,，小組證實(shí)含有人類CEH基因的老鼠能通過(guò)去除血管凝集的泡沫狀細(xì)胞中膽固醇來(lái)大大降低心臟病風(fēng)險(xiǎn)。
Ghosh說(shuō)：“目前治療心臟病的重點(diǎn)在于減少循環(huán)系統(tǒng)中的LDL,。而我們的研究證明如果能增加粥樣斑塊中膽固醇的去除量,，那么即使不改變LDL濃度粥樣斑塊也會(huì)大大減少,。這些發(fā)現(xiàn)不但改變了目前對(duì)心臟病治療的想法，通過(guò)將CEH作為治療目標(biāo),，未來(lái)心臟病人能得到更好的治療手段,。除此之外，利用人類血液細(xì)胞中CEH濃度,，我們希望能預(yù)測(cè)心臟病發(fā)生幾率,。”
Ghosh表示，小組研究重點(diǎn)在于泡沫狀巨噬細(xì)胞,，這是儲(chǔ)存大量膽固醇并導(dǎo)致動(dòng)脈粥樣沉積和阻塞的原因,。以上結(jié)果發(fā)表在10月份的《臨床檢查雜志》（The Journal of Clinical Investigation）上。（教育部科技發(fā)展中心）
原始出處:
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: [email protected] .
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.
