Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension.
Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension.
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DOI：
10.1161/circulationaha.113.001585
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发表时间：
2013-07-30
期刊：
影响因子：
37.8
通讯作者：
Leopold JA
中科院分区：
文献类型：
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作者：
Hadri L;Kratlian RG;Benard L;Maron BA;Dorfmüller P;Ladage D;Guignabert C;Ishikawa K;Aguero J;Ibanez B;Turnbull IC;Kohlbrenner E;Liang L;Zsebo K;Humbert M;Hulot JS;Kawase Y;Hajjar RJ;Leopold JA
肺动脉高压（PAH）的特征是肺动脉平滑肌细胞增殖失调，导致（不正常的）适应性血管重构。在体循环中，血管损伤与肌浆网Ca2+- atp酶2a （SERCA2a）的下调和血管平滑肌细胞Ca2+稳态的改变有关，从而刺激增殖。因此，我们假设SERCA2a的下调对肺血管重构和PAH的发展是有利的。与对照组相比，PAH患者和PAH单肽模型大鼠重建肺动脉中SERCA2a的表达显著降低。在体外培养的人肺动脉平滑肌细胞中，通过基因转移过表达SERCA2a可通过抑制NFAT/STAT3显著降低细胞增殖和迁移。SERCA2a在体外培养的人肺动脉内皮细胞中过表达可增加内皮型一氧化氮合酶的表达和激活。在已建立的PAH大鼠中，通过气管内递送携带人类SERCA2a基因（AAV1.SERCA2a）的雾化腺相关病毒血清型1 （AAV1）的SERCA2a基因转移，与使用携带β-半乳糖苷酶或生理盐水的对照AAV1治疗的单星碱-PAH大鼠相比，降低了肺动脉压、血管重构、右心室肥大和纤维化。在预防方案中，雾化AAV1。与携带β-半乳糖苷酶或生理盐水给药的AAV1相比，在给药时递送SERCA2a限制了不良血流动力学特征和肺和心脏重构指标。SERCA2a的下调在调节与PAH相关的血管和右心室病理表型中起关键作用。选择性肺SERCA2a基因转移可能作为PAH的治疗干预提供益处。
Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and alterations in Ca2+ homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH. SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying β-galactosidase or saline. Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.