Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension
Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertension
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DOI：
10.1161/circulationaha.105.540542
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发表时间：
2005-07-19
期刊：
影响因子：
37.8
通讯作者：
Rabinovitch, M
中科院分区：
文献类型：
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作者：
Merklinger, SL;Jones, PL;Rabinovitch, M
背景-我们以前报道过弹性蛋白酶抑制剂通过诱导平滑肌细胞凋亡逆转大鼠致死性肺动脉高压。我们在肺动脉（PA）器官培养中发现，弹性蛋白酶抑制剂诱导SMC凋亡的机制涉及抑制基质金属蛋白酶（MMP）活性和随后通过α（v）β（3）-整合素和表皮生长因子受体（EGFR）的信号传导。这表明，这些下游效应的封锁也可能会导致PAH.Methods和结果的回归-在这项研究中，我们首先表明，在PA器官培养MMP抑制或α（V）β（3）-整联蛋白封锁剂在临床和临床前使用（SC-080和cilengitide，分别）介导SMC凋亡和中膜肥大的回归。我们还记录了EGFR酪氨酸激酶抑制剂的类似结果。然后，我们通过注射野百合碱诱导大鼠PAH，并在第21天开始用SC-080、西仑吉肽或EGFR抑制剂PKI 166治疗2周。溶媒或西仑吉肽处理的动物均未存活超过2周。SC-080给药导致2周时44%的存活率，PKI 166治疗导致每日或每周3次治疗的动物分别有78%和54%的存活率。四个星期后停止PKI 166，我们记录的生存率为50%和23%，在2个治疗组，与肺动脉压，右心室肥大，和异常肌化远端arteries.Conclusion减少，我们建议选择性阻断EGFR信号可能是一种新的策略，以扭转进行性，致命的PAH。
Background - We previously reported that administration of elastase inhibitors reverses fatal pulmonary arterial hypertension (PAH) in rats by inducing smooth muscle cell (SMC) apoptosis. We showed in pulmonary artery (PA) organ culture that the mechanism by which elastase inhibitors induce SMC apoptosis involves repression of matrix metalloproteinase (MMP) activity and subsequent signaling through alpha(v)beta(3)-integrins and epidermal growth factor receptors (EGFRs). This suggests that blockade of these downstream effectors may also induce regression of PAH.Methods and Results - In this study, we first showed in PA organ culture that MMP inhibition or alpha(v)beta(3)-integrin blockade with agents in clinical and preclinical use ( SC-080 and cilengitide, respectively) mediates SMC apoptosis and regression of medial hypertrophy. We also documented similar results with an EGFR tyrosine kinase inhibitor. We then induced PAH in rats by injection of monocrotaline and, at day 21, began a 2-week treatment with SC-080, cilengitide, or the EGFR inhibitor PKI166. No vehicle-or cilengitide-treated animal survived beyond 2 weeks. Administration of SC-080 resulted in 44% survival at 2 weeks, and PKI166 therapy resulted in 78% and 54% survival in daily or 3-times-weekly treated animals, respectively. Four weeks after cessation of PKI166, we documented survivals of 50% and 23% in the 2 treatment groups, associated with reductions in pulmonary pressure, right ventricular hypertrophy, and abnormally muscularized distal arteries.Conclusion - We propose that selective blockade of EGFR signaling may be a novel strategy to reverse progressive, fatal PAH.