Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy
Short-term administration of a cell-permeable caveolin-1 peptide prevents the development of monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy
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DOI：
10.1161/circulationaha.106.634709
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发表时间：
2006-08-29
期刊：
影响因子：
37.8
通讯作者：
Lisanti, Michael P.
中科院分区：
文献类型：
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作者：
Jasmin, Jean-Francois;Mercier, Isabelle;Lisanti, Michael P.
背景-空泡微区的主要结构蛋白小窝蛋白(Caveolins，Cavs)与肺动脉高压(PH)的发生发展密切相关。Cav-1基因纯合缺失的小鼠会发生PH和右室肥厚(RVH)。在几种肺高压动物模型和重度肺高压患者中，肺Cav-1的表达已经显示减少。Cav-1在体内的表达调控是否会影响PH和RVH的发生，目前尚不清楚。因此，我们研究了体内注射Cav-1模拟肽对野百合碱(MCT)诱导的PH形成的影响。方法和结果-注射生理盐水或60 mg/kg MCT后30分钟，大鼠每天注射生理盐水，这是一种与果蝇转录因子触角蛋白(AP)同源结构域对应的肽(AP；2.5 mg(.)Kg(-1)d(-1))，或由Cav-1-支架结构域与AP偶联的多肽(AP-Cav；2.5 mg(.)kg(-1)d(-1))，持续2周。MCT组和MCT+AP组大鼠右室收缩压分别为40.2+/-1.5和39.6+/-1.5 mm Hg。给MCT大鼠注射AP-Cav可显著降低右室收缩压至30.1±1.3 mm Hg。MCT和MCT+AP大鼠也出现了肺动脉中层肥厚和RVH，应用AP-Cav可使其恢复正常。从机制上讲，肺组织Cav-1和Cav-2的表达减少、STAT3信号转导通路的过度激活以及细胞周期蛋白D1和D3蛋白水平的上调均可被AP-Cav.结论短期给药可预防MCT大鼠肺动脉中层肥厚、PH和RVH的发生。
Background-Caveolins (Cavs), the principal structural proteins of caveolar microdomains, have been implicated in the development of pulmonary hypertension (PH). Mice with homozygous deletion of the Cav-1 gene develop PH and right ventricular hypertrophy (RVH). Reductions in pulmonary Cav-1 expression have been shown in several animal models of PH and in patients with severe PH. Whether in vivo modulation of Cav-1 expression could affect the development of PH and RVH remains unknown. Therefore, we investigated the effect of in vivo administration of a Cav-1 mimetic peptide on the development of monocrotaline (MCT)-induced PH.Methods and Results-Thirty minutes after injection of saline or 60 mg/ kg MCT, rats were assigned to receive a daily injection of saline, a peptide corresponding to the homeodomain of the Drosophila transcription factor antennapedia (AP; 2.5 mg (.) kg(-1.)d(-1)), or a peptide consisting of the Cav-1-scaffolding domain coupled to AP (AP-Cav; 2.5 mg(.)kg(-1.)d(-1)) for 2 weeks. MCT and MCT + AP rats developed PH with respective right ventricular systolic pressures of 40.2 +/- 1.5 and 39.6 +/- 1.5 mm Hg. Administration of AP-Cav to MCT rats significantly reduced the right ventricular systolic pressure to 30.1 +/- 1.3 mm Hg. MCT and MCT + AP rats also developed pulmonary artery medial hypertrophy and RVH, which was normalized by administration of AP-Cav. Mechanistically, the development of PH was associated with reduced expression of pulmonary Cav-1 and Cav-2, hyperactivation of the STAT3 signaling cascade, and upregulation of cyclin D1 and D3 protein levels, all of which were prevented by administration of AP-Cav.Conclusions-Short-term administration of a Cav-based cell-permeable peptide to MCT rats prevents the development of pulmonary artery medial hypertrophy, PH, and RVH.