RGD Reference Report - Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. - Rat Genome Database

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

Authors: McMurtry, MS  Archer, SL  Altieri, DC  Bonnet, S  Haromy, A  Harry, G 
Citation: McMurtry MS, etal., J Clin Invest. 2005 Jun;115(6):1479-91.
RGD ID: 2293135
Pubmed: PMID:15931388   (View Abstract at PubMed)
PMCID: PMC1136986   (View Article at PubMed Central)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
BIRC5Humanpulmonary hypertension  ISOBirc5 (Rattus norvegicus) RGD 
BIRC5Humanpulmonary hypertension  IEP protein:increased expression:pulmonary arteryRGD 
Birc5Ratpulmonary hypertension  IEP protein:increased expression:pulmonary arteryRGD 
Birc5Ratpulmonary hypertension  IMP  RGD 
Birc5Mousepulmonary hypertension  ISOBirc5 (Rattus norvegicus) RGD 
Birc5Mousepulmonary hypertension  ISOBirc5 (Rattus norvegicus) and BIRC5 (Homo sapiens)protein:increased expression:pulmonary arteryRGD 

Objects Annotated

Genes (Rattus norvegicus)
Birc5  (baculoviral IAP repeat-containing 5)

Genes (Mus musculus)
Birc5  (baculoviral IAP repeat-containing 5)

Genes (Homo sapiens)
BIRC5  (baculoviral IAP repeat containing 5)


Additional Information