Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension
Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension
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DOI：
10.1172/jci23203
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发表时间：
2005-06-01
影响因子：
15.9
通讯作者：
Michelakis, ED
中科院分区：
文献类型：
--
作者：
McMurtry, MS;Archer, SL;Michelakis, ED
肺动脉高压（PAH）的特征是遗传性和获得性异常，这些异常抑制血管壁中的细胞凋亡并增强细胞增殖，包括骨形态发生蛋白轴和电压门控K+（Kv）通道的下调。生存素是一种“凋亡抑制剂”蛋白，以前认为主要在癌细胞中表达。结果发现，6例PAH患者和野百合碱诱导的PAH大鼠的肺动脉（PA）中有Survivin表达，而3例患者和非PAH大鼠的PA中无Survivin表达。吸入携带磷酸化缺陷型生存素突变体的腺病毒进行基因治疗可逆转已建立的野百合碱诱导的PAH，并使生存期延长25%。生存素突变体降低肺血管阻力、右心室肥大和肺动脉中膜肥大。在体外和体内，抑制生存素诱导PA平滑肌细胞凋亡，减少增殖，线粒体去极化，引起细胞质中的细胞色素c流出和凋亡诱导因子易位到细胞核中，并增加Kv通道电流;与WT生存素的基因转移，在体内和体外观察到相反的效果。抑制伴随人类和实验性PAH的生存素的不适当表达是一种新的治疗策略，其通过诱导血管内皮依赖性细胞凋亡起作用。
Pulmonary arterial hypertension (PAH) is characterized by genetic and acquired abnormalities that suppress apoptosis and enhance cell proliferation in the vascular wall, including downregulation of the bone morphogenetic protein axis and voltage-gated K+ (Kv) channels. Survivin is an "inhibitor of apoptosis" protein, previously thought to be expressed primarily in cancer cells. We found that survivin was expressed in the pulmonary arteries (PAs) of 6 patients with PAH and rats with monocrotaline-induced PAH, but not in the PAs of 3 patients and rats without PAH. Gene therapy with inhalation of an adenovirus carrying a phosphorylation-deficient survivin mutant with dominant-negative properties reversed established monocrotaline-induced PAH and prolonged survival by 25%. The survivin mutant lowered pulmonary vascular resistance, RV hypertrophy, and PA medial hypertrophy. Both in vitro and in vivo, inhibition of survivin induced PA smooth muscle cell apoptosis, decreased proliferation, depolarized mitochondria, caused efflux of cytochrome c in the cytoplasm and translocation of apoptosis-inducing factor into the nucleus, and increased Kv channel current; the opposite effects were observed with gene transfer of WT survivin, both in vivo and in vitro. Inhibition of the inappropriate expression of survivin that accompanies human and experimental PAH is a novel therapeutic strategy that acts by inducing vascular mitochondria-dependent apoptosis.