Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension.
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.
McMurtry
M Sean
MS
The Vascular Biology Group and Pulmonary Hypertension Program, University of Alberta, Edmonton, Alberta, Canada.
Archer
Stephen L
SL
Altieri
Dario C
DC
Bonnet
Sebastien
S
Haromy
Alois
A
Harry
Gwyneth
G
Bonnet
Sandra
S
Puttagunta
Lakshmi
L
Michelakis
Evangelos D
ED
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
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