title: Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension.
abstract: 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.
authors.affiliation: The Vascular Biology Group and Pulmonary Hypertension Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: M Sean
authors.initials: MS
authors.lastname: McMurtry
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.forename: Sebastien
authors.initials: S
authors.lastname: Bonnet
authors.forename: Alois
authors.initials: A
authors.lastname: Haromy
authors.forename: Gwyneth
authors.initials: G
authors.lastname: Harry
authors.forename: Sandra
authors.initials: S
authors.lastname: Bonnet
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Puttagunta
authors.forename: Evangelos D
authors.initials: ED
authors.lastname: Michelakis
mesh_terms: D000256:Adenoviridae; D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045304:Cytochromes c / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005799:Genes, Dominant; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009363:Neoplasm Proteins; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077022:Survivin; D014655:Vascular Resistance
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D024642:Potassium Channels, Voltage-Gated; D000077022:Survivin; D045304:Cytochromes c