AAV-PGIS gene transfer improves hypoxia-induced pulmonary hypertension in mice.
Although prostaglandin I2 is used to treat pulmonary hypertension (PH), continuous intravenous administration is necessary. We investigated whether human PGIS (hPGIS) gene transfer using adeno-associated virus (AAV) vector was effective in treating an animal model of PH. PH was induced by subjecting mice to 10% O(2). Type 1-AAV-hPGIS was injected into the left thigh muscle after 24h. Significant PH was induced at 8 weeks, but AAV-hPGIS administration significantly inhibited the increase in RV systolic pressure. PH-induced BNP up-regulation in the RV was reduced to the control level. The severe medial thickening of pulmonary arteries in PH was significantly suppressed by AAV-hPGIS. The hPGIS gene was detected only on the injected side. No pathological changes were observed at the injected site. At 24 weeks, all PH mice were deceased, but 47% of AAV-hPGIS-treated mice survived. This study demonstrated that AAV-hPGIS administration was effective in treating PH and prolonging survival.
Kawakami
Takashi
T
Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Kanazawa
Hideaki
H
Satoh
Toru
T
Ieda
Masaki
M
Ieda
Yasuyo
Y
Kimura
Kensuke
K
Mochizuki
Hideki
H
Shimada
Takashi
T
Yokoyama
Chieko
C
Ogawa
Satoshi
S
Tanabe
Tadashi
T
Fukuda
Keiichi
K
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics*; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology / Q000628:therapy*; D017380:Hypertrophy, Right Ventricular / Q000473:pathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D041681:NIH 3T3 Cells; D009929:Organ Size; D011401:Promoter Regions, Genetic / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014162:Transfection / Q000379:methods
D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D015121:6-Ketoprostaglandin F1 alpha; D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase