Cipollone Francesco, Fazia Maria, Iezzi Annalisa, Zucchelli Mirco, Pini Barbara, De Cesare Domenico, Ucchino Sante, Spigonardo Francesco, Bajocchi Guido, Bei Roberto, Muraro Raffaella, Artese Luciano, Piattelli Adriano, Chiarelli Francesco, Cuccurullo Franco, Mezzetti Andrea
Department of Medicine and Aging, School of Medicine, University of Chieti G. d'Annunzio, Chieti, Italy.
Circulation. 2003 Mar 25;107(11):1479-85. doi: 10.1161/01.cir.0000056530.03783.81.
The clinical benefits of statins are attributed to changes in plaque composition that lead to reduced metalloproteinase (MMP) activity and plaque stabilization. However, the molecular mechanism of this effect is unclear. Recently, we demonstrated enhanced expression of isoforms of inducible cyclooxygenase (COX) and PGE synthase (COX-2/mPGES) in human symptomatic plaque and provided evidence that this is associated with MMP-induced plaque rupture. The aim of this study was to characterize the effect of simvastatin on inflammatory infiltration and the expression of COX-2/mPGES and MMPs in human carotid plaques.
Seventy patients with symptomatic carotid artery stenosis were randomized to the American Heart Association Step 1 diet plus simvastatin (40 mg/d) or the American Heart Association Step 1 diet alone for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES, MMP-2 and MMP-9, lipid and oxidized LDL (oxLDL) content, and collagen content by immunocytochemistry, Western blot, and reverse transcription-polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunocytochemistry was also used to identify CD68+ macrophages, CD3+ T-lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Plaques from the simvastatin group had fewer (P<0.0001) macrophages, T-lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity for COX-2/mPGES and MMPs; reduced (P<0.0001) gelatinolytic activity; increased (P<0.0001) collagen content; and reduced (P<0.0001) lipid and oxLDL content. Interestingly, COX-2/mPGES inhibition by simvastatin was completely reversed by mevalonate in vitro.
This study demonstrates that simvastatin decreases inflammation and inhibits COX-2/mPGES expression in plaque macrophages, and this effect in turn may contribute to plaque stabilization by inhibition of MMP-induced plaque rupture.
他汀类药物的临床益处归因于斑块成分的改变，这种改变导致金属蛋白酶（MMP）活性降低和斑块稳定。然而，这种作用的分子机制尚不清楚。最近，我们证明了诱导型环氧化酶（COX）和前列腺素E合酶（COX-2/mPGES）同工型在人类有症状斑块中的表达增强，并提供证据表明这与MMP诱导的斑块破裂有关。本研究的目的是描述辛伐他汀对人类颈动脉斑块中炎症浸润以及COX-2/mPGES和MMPs表达的影响。
70例有症状颈动脉狭窄患者在接受动脉内膜切除术前行随机分组，分别给予美国心脏协会一级饮食加辛伐他汀（40mg/d）或单纯美国心脏协会一级饮食，为期4个月。通过免疫细胞化学、蛋白质印迹法和逆转录-聚合酶链反应对斑块进行COX-1、COX-2、mPGES、MMP-2和MMP-9、脂质和氧化型低密度脂蛋白（oxLDL）含量以及胶原含量的分析，而用酶谱法检测MMP活性。免疫细胞化学还用于鉴定CD68+巨噬细胞、CD3+T淋巴细胞、平滑肌细胞（SMC）和HLA-DR+炎症细胞。辛伐他汀组的斑块中巨噬细胞、T淋巴细胞和HLA-DR+细胞较少（P<0.0001）；COX-2/mPGES和MMPs免疫反应性较低（P<0.0001）；明胶酶活性降低（P<0.0001）；胶原含量增加（P<0.0001）；脂质和oxLDL含量降低（P<0.0001）。有趣的是，在体外甲羟戊酸可完全逆转辛伐他汀对COX-2/mPGES的抑制作用。
本研究表明辛伐他汀可减轻炎症并抑制斑块巨噬细胞中COX-2/mPGES的表达，而这种作用反过来可能通过抑制MMP诱导的斑块破裂促进斑块稳定。
