Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension

被引:295
作者
McMurtry, MS
Archer, SL
Altieri, DC
Bonnet, S
Haromy, A
Harry, G
Bonnet, S
Puttagunta, L
Michelakis, ED [1 ]
机构
[1] Univ Alberta, Pulm Hypertens Program, Edmonton, AB T6G 2B7, Canada
[2] Univ Alberta, Vasc Biol Grp, Edmonton, AB T6G 2B7, Canada
[3] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA
[4] Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA 01605 USA
[5] Univ Alberta, Dept Pathol, Edmonton, AB T6G 2E1, Canada
关键词
D O I
10.1172/JCI23203
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
引用
收藏
页码:1479 / 1491
页数:13
相关论文
共 44 条
[1]   Long-term treatment with a Rho-kinase inhibitor improves monocrotaline-induced fatal pulmonary hypertension in rats [J].
Abe, K ;
Shimokawa, H ;
Morikawa, K ;
Uwatoku, T ;
Oi, K ;
Matsumoto, Y ;
Hattori, T ;
Nakashima, Y ;
Kaibuchi, K ;
Sueishi, K ;
Takeshita, A .
CIRCULATION RESEARCH, 2004, 94 (03) :385-393
[2]   Validating survivin as a cancer therapeutic target [J].
Altieri, DC .
NATURE REVIEWS CANCER, 2003, 3 (01) :46-54
[3]   Primary pulmonary hypertension - A vascular biology and translational research "work in progress" [J].
Archer, S ;
Rich, S .
CIRCULATION, 2000, 102 (22) :2781-2791
[4]   Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes [J].
Archer, SL ;
Souil, E ;
Dinh-Xuan, AT ;
Schremmer, B ;
Mercier, JC ;
El Yaagoubi, A ;
Nguyen-Huu, L ;
Reeve, HL ;
Hampl, V .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 101 (11) :2319-2330
[5]   ALTERATIONS OF GROWTH-FACTOR TRANSCRIPTS IN RAT LUNGS DURING DEVELOPMENT OF MONOCROTALINE-INDUCED PULMONARY-HYPERTENSION [J].
ARCOT, SS ;
LIPKE, DW ;
GILLESPIE, MN ;
OLSON, JW .
BIOCHEMICAL PHARMACOLOGY, 1993, 46 (06) :1086-1091
[6]   Inhibitor of apoptosis protein survivin regulates vascular injury [J].
Blanc-Brude, OP ;
Yu, J ;
Simosa, H ;
Conte, MS ;
Sessa, WC ;
Altieri, DC .
NATURE MEDICINE, 2002, 8 (09) :987-994
[7]   Endothelial dysfunction in pulmonary hypertension [J].
Budhiraja, R ;
Tuder, RM ;
Hassoun, PM .
CIRCULATION, 2004, 109 (02) :159-165
[8]   HYDROGEN-PEROXIDE ELICITS PULMONARY ARTERIAL RELAXATION AND GUANYLATE-CYCLASE ACTIVATION [J].
BURKE, TM ;
WOLIN, MS .
AMERICAN JOURNAL OF PHYSIOLOGY, 1987, 252 (04) :H721-H732
[9]   Hydrogen peroxide modulates the Kv1.5 channel expressed in a mammalian cell line [J].
Caouette, D ;
Dongmo, C ;
Bérubé, J ;
Fournier, D ;
Daleau, P .
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 2003, 368 (06) :479-486
[10]   Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor [J].
Cowan, KN ;
Heilbut, A ;
Humpl, T ;
Lam, C ;
Ito, S ;
Rabinovitch, M .
NATURE MEDICINE, 2000, 6 (06) :698-702