AAV-PGIS gene transfer improves hypoxia-induced pulmonary hypertension in mice

Takashi Kawakami; Hideaki Kanazawa; Toru Satoh; Masaki Ieda; Yasuyo Ieda; Kensuke Kimura; Hideki Mochizuki; Takashi Shimada; Chieko Yokoyama; Satoshi Ogawa; Tadashi Tanabe; Keiichi Fukuda

doi:10.1016/j.bbrc.2007.09.039

AAV-PGIS gene transfer improves hypoxia-induced pulmonary hypertension in mice

Biochem Biophys Res Commun. 2007 Nov 23;363(3):656-61. doi: 10.1016/j.bbrc.2007.09.039. Epub 2007 Sep 20.

Authors

Takashi Kawakami¹, Hideaki Kanazawa, Toru Satoh, Masaki Ieda, Yasuyo Ieda, Kensuke Kimura, Hideki Mochizuki, Takashi Shimada, Chieko Yokoyama, Satoshi Ogawa, Tadashi Tanabe, Keiichi Fukuda

Affiliation

¹ Department of Regenerative Medicine and Advanced Cardiac Therapeutics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

PMID: 17904526
DOI: 10.1016/j.bbrc.2007.09.039

Abstract

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.

MeSH terms

6-Ketoprostaglandin F1 alpha / metabolism
Animals
Cytochrome P-450 Enzyme System / genetics
Cytochrome P-450 Enzyme System / metabolism*
Dependovirus / genetics*
Gene Expression
Genetic Therapy / methods
Genetic Vectors / genetics
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Humans
Hypertension, Pulmonary / etiology
Hypertension, Pulmonary / pathology
Hypertension, Pulmonary / therapy*
Hypertrophy, Right Ventricular / pathology
Hypertrophy, Right Ventricular / prevention & control
Hypoxia / complications*
Intramolecular Oxidoreductases / genetics
Intramolecular Oxidoreductases / metabolism*
Lung / metabolism
Lung / pathology
Male
Mice
Mice, Inbred C57BL
Microscopy, Fluorescence
Muscle, Skeletal / metabolism
Muscle, Skeletal / pathology
NIH 3T3 Cells
Organ Size
Promoter Regions, Genetic / genetics
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Survival Analysis
Transfection / methods

Substances

Recombinant Fusion Proteins
Green Fluorescent Proteins
6-Ketoprostaglandin F1 alpha
Cytochrome P-450 Enzyme System
Intramolecular Oxidoreductases
prostacyclin synthetase