Cipollone Francesco, Fazia Maria, Iezzi Annalisa, Pini Barbara, Cuccurullo Chiara, Zucchelli Mirco, de Cesare Domenico, Ucchino Sante, Spigonardo Francesco, De Luca Mariella, Muraro Raffaella, Bei Roberto, Bucci Marco, Cuccurullo Franco, Mezzetti Andrea
G. d'Annunzio University of Chieti and the G. d'Annunzio University Foundation, Chieti, Italy.
Circulation. 2004 Mar 30;109(12):1482-8. doi: 10.1161/01.CIR.0000121735.52471.AC. Epub 2004 Mar 22.
Clinical trials have demonstrated that agents that inhibit the angiotensin II pathway confer benefit beyond the reduction of blood pressure alone. However, the molecular mechanism underlying this effect has yet to be investigated. Recently, we have demonstrated enhanced expression of inducible cyclooxygenase (COX) and prostaglandin (PG)E2-dependent synthase (COX-2/mPGES-1) in human symptomatic plaques and provided evidence that it is associated with metalloproteinase (MMP)-induced plaque rupture. Thus, the aim of this study was to characterize the effect of the angiotensin II type 1 (AT1) receptor antagonist irbesartan on the inflammatory infiltration and expression of COX-2/mPGES-1 and MMPs in human carotid plaques.
Seventy patients with symptomatic carotid artery stenosis were randomized to irbesartan (300 mg/d) or chlorthalidone (50 mg/d) for 4 months before endarterectomy. Plaques were subjected to analysis of COX-1, COX-2, mPGES-1, MMP-2, and MMP-9, angiotensin II, AT(1), AT2, and collagen content by immunocytochemistry, Western blot, and reverse-transcriptase polymerase chain reaction, whereas zymography was used to detect MMP activity. Immunohistochemistry was also used to identify CD68+ macrophages, CD3+ T lymphocytes, smooth muscle cells (SMCs), and HLA-DR+ inflammatory cells. Plaques from the irbesartan group had fewer (P<0.0001) macrophages, T lymphocytes, and HLA-DR+ cells; less (P<0.0001) immunoreactivity for COX-2/mPGES-1 and MMPs; reduced (P<0.0001) gelatinolytic activity; and increased (P<0.0001) collagen content. It is worth noting that COX-2/mPGES-1 inhibition was observed after incubation in vitro with irbesartan but not with the selective AT2 blockade PD123,319.
This study demonstrates that irbesartan decreases inflammation and inhibits COX-2/mPGES-1 expression in plaque macrophages, and this effect may in turn contribute to plaque stabilization by inhibition of MMP-induced plaque rupture.
临床试验表明，抑制血管紧张素II途径的药物所带来的益处不仅仅是单纯降低血压。然而，这种效应背后的分子机制尚未得到研究。最近，我们已经证实在有症状的人类斑块中诱导型环氧化酶（COX）和前列腺素（PG）E2依赖性合酶（COX-2/mPGES-1）表达增强，并提供证据表明其与金属蛋白酶（MMP）诱导的斑块破裂有关。因此，本研究的目的是明确血管紧张素II 1型（AT1）受体拮抗剂厄贝沙坦对人类颈动脉斑块中炎症浸润以及COX-2/mPGES-1和MMPs表达的影响。
70例有症状的颈动脉狭窄患者在接受动脉内膜切除术之前被随机分为厄贝沙坦组（300mg/d）或氯噻酮组（50mg/d），治疗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-1、MMP-2和MMP-9、血管紧张素II、AT(1)、AT2以及胶原蛋白含量的分析，而酶谱法用于检测MMP活性。免疫组织化学也用于鉴定CD68+巨噬细胞、CD3+ T淋巴细胞、平滑肌细胞（SMC）和HLA-DR+炎症细胞。厄贝沙坦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-1和MMPs的免疫反应性较低（P<0.0001）；明胶酶活性降低（P<0.0001）；胶原蛋白含量增加（P<0.0001）。值得注意的是，在体外与厄贝沙坦孵育后观察到COX-2/mPGES-1受到抑制，但与选择性AT2阻滞剂PD123,319孵育后未观察到这种抑制作用。
本研究表明，厄贝沙坦可减轻炎症并抑制斑块巨噬细胞中COX-2/mPGES-1的表达，而这种效应可能通过抑制MMP诱导的斑块破裂进而有助于斑块稳定。
