Gene transfer therapy by either type 1 or type 2 adeno-associated virus expressing human prostaglandin I2 synthase gene is effective for treatment of pulmonary arterial hypertension

Masaharu Kataoka, Takashi Kawakami, Yuichi Tamura, Hideaki Yoshino, Toru Satoh, Tadashi Tanabe, Keiichi Fukuda

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Prostaglandin I2 (PGI2) plays an important role in the clinical treatment of pulmonary arterial hypertension (PAH). However, the administration of PGI2 involves continuous intravenous infusion using an indwelling catheter, which limits the patient's quality of life and increases the risk of infection. We therefore investigated whether human PGI2 synthase (hPGIS) gene transfer using an adeno-associated virus (AAV) vector is still effective in a mouse model of PAH and tested for differences in the therapeutic efficacy of PAH among AAV serotypes. The PAH was induced by subjecting mice to hypoxia (10% O2). Type 1 AAV expressing hPGIS (AAV1-hPGIS) or type 2 AAV expressing hPGIS (AAV2-hPGIS) was injected into the thigh muscle of mice. Both vectors expressing hPGIS produced strong hPGIS protein expression in the mouse thigh skeletal muscles after 8 weeks of hypoxia. The administration of AAV1-hPGIS or AAV2-hPGIS also significantly inhibited the hypoxia-induced increase in right ventricular systolic pressure, the ratio of right ventricular weight to body weight (RV/BW), and the ratio of RV weight to left ventricular plus septal weight (RV/LV + S), and significantly attenuated the hypoxia-induced increase in medial wall thickness of peripheral pulmonary arteries. Furthermore, there were no significant differences in the degree of amelioration in RV systolic pressure, RV/BW, RV/LV + S, and percentage of wall thickness of peripheral pulmonary arteries between AAV1-hPGIS and AAV2-hPGIS administrations. In conclusion, we revealed that type 1 and type 2 AAV are equally effective for the treatment of PAH in a hypoxia-induced mouse model. Gene-transfer therapy using AAV expressing hPGIS is, therefore, a potential therapeutic breakthrough for PAH.

Original languageEnglish
Pages (from-to)54-59
Number of pages6
JournalJournal of Cardiovascular Pharmacology and Therapeutics
Volume18
Issue number1
DOIs
Publication statusPublished - 2013 Jan

Fingerprint

Dependovirus
Epoprostenol
Prostaglandin-Endoperoxide Synthases
Pulmonary Hypertension
Genetic Therapy
Genes
Therapeutics
Weights and Measures
Thigh
Pulmonary Artery
prostacyclin synthetase
Body Weight
Blood Pressure
Indwelling Catheters
Ventricular Pressure
Intravenous Infusions
Skeletal Muscle

Keywords

  • adeno-associated virus
  • gene transfer
  • prostaglandin I2 synthase
  • pulmonary arterial hypertension

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

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title = "Gene transfer therapy by either type 1 or type 2 adeno-associated virus expressing human prostaglandin I2 synthase gene is effective for treatment of pulmonary arterial hypertension",
abstract = "Prostaglandin I2 (PGI2) plays an important role in the clinical treatment of pulmonary arterial hypertension (PAH). However, the administration of PGI2 involves continuous intravenous infusion using an indwelling catheter, which limits the patient's quality of life and increases the risk of infection. We therefore investigated whether human PGI2 synthase (hPGIS) gene transfer using an adeno-associated virus (AAV) vector is still effective in a mouse model of PAH and tested for differences in the therapeutic efficacy of PAH among AAV serotypes. The PAH was induced by subjecting mice to hypoxia (10{\%} O2). Type 1 AAV expressing hPGIS (AAV1-hPGIS) or type 2 AAV expressing hPGIS (AAV2-hPGIS) was injected into the thigh muscle of mice. Both vectors expressing hPGIS produced strong hPGIS protein expression in the mouse thigh skeletal muscles after 8 weeks of hypoxia. The administration of AAV1-hPGIS or AAV2-hPGIS also significantly inhibited the hypoxia-induced increase in right ventricular systolic pressure, the ratio of right ventricular weight to body weight (RV/BW), and the ratio of RV weight to left ventricular plus septal weight (RV/LV + S), and significantly attenuated the hypoxia-induced increase in medial wall thickness of peripheral pulmonary arteries. Furthermore, there were no significant differences in the degree of amelioration in RV systolic pressure, RV/BW, RV/LV + S, and percentage of wall thickness of peripheral pulmonary arteries between AAV1-hPGIS and AAV2-hPGIS administrations. In conclusion, we revealed that type 1 and type 2 AAV are equally effective for the treatment of PAH in a hypoxia-induced mouse model. Gene-transfer therapy using AAV expressing hPGIS is, therefore, a potential therapeutic breakthrough for PAH.",
keywords = "adeno-associated virus, gene transfer, prostaglandin I2 synthase, pulmonary arterial hypertension",
author = "Masaharu Kataoka and Takashi Kawakami and Yuichi Tamura and Hideaki Yoshino and Toru Satoh and Tadashi Tanabe and Keiichi Fukuda",
year = "2013",
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T1 - Gene transfer therapy by either type 1 or type 2 adeno-associated virus expressing human prostaglandin I2 synthase gene is effective for treatment of pulmonary arterial hypertension

AU - Kataoka, Masaharu

AU - Kawakami, Takashi

AU - Tamura, Yuichi

AU - Yoshino, Hideaki

AU - Satoh, Toru

AU - Tanabe, Tadashi

AU - Fukuda, Keiichi

PY - 2013/1

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N2 - Prostaglandin I2 (PGI2) plays an important role in the clinical treatment of pulmonary arterial hypertension (PAH). However, the administration of PGI2 involves continuous intravenous infusion using an indwelling catheter, which limits the patient's quality of life and increases the risk of infection. We therefore investigated whether human PGI2 synthase (hPGIS) gene transfer using an adeno-associated virus (AAV) vector is still effective in a mouse model of PAH and tested for differences in the therapeutic efficacy of PAH among AAV serotypes. The PAH was induced by subjecting mice to hypoxia (10% O2). Type 1 AAV expressing hPGIS (AAV1-hPGIS) or type 2 AAV expressing hPGIS (AAV2-hPGIS) was injected into the thigh muscle of mice. Both vectors expressing hPGIS produced strong hPGIS protein expression in the mouse thigh skeletal muscles after 8 weeks of hypoxia. The administration of AAV1-hPGIS or AAV2-hPGIS also significantly inhibited the hypoxia-induced increase in right ventricular systolic pressure, the ratio of right ventricular weight to body weight (RV/BW), and the ratio of RV weight to left ventricular plus septal weight (RV/LV + S), and significantly attenuated the hypoxia-induced increase in medial wall thickness of peripheral pulmonary arteries. Furthermore, there were no significant differences in the degree of amelioration in RV systolic pressure, RV/BW, RV/LV + S, and percentage of wall thickness of peripheral pulmonary arteries between AAV1-hPGIS and AAV2-hPGIS administrations. In conclusion, we revealed that type 1 and type 2 AAV are equally effective for the treatment of PAH in a hypoxia-induced mouse model. Gene-transfer therapy using AAV expressing hPGIS is, therefore, a potential therapeutic breakthrough for PAH.

AB - Prostaglandin I2 (PGI2) plays an important role in the clinical treatment of pulmonary arterial hypertension (PAH). However, the administration of PGI2 involves continuous intravenous infusion using an indwelling catheter, which limits the patient's quality of life and increases the risk of infection. We therefore investigated whether human PGI2 synthase (hPGIS) gene transfer using an adeno-associated virus (AAV) vector is still effective in a mouse model of PAH and tested for differences in the therapeutic efficacy of PAH among AAV serotypes. The PAH was induced by subjecting mice to hypoxia (10% O2). Type 1 AAV expressing hPGIS (AAV1-hPGIS) or type 2 AAV expressing hPGIS (AAV2-hPGIS) was injected into the thigh muscle of mice. Both vectors expressing hPGIS produced strong hPGIS protein expression in the mouse thigh skeletal muscles after 8 weeks of hypoxia. The administration of AAV1-hPGIS or AAV2-hPGIS also significantly inhibited the hypoxia-induced increase in right ventricular systolic pressure, the ratio of right ventricular weight to body weight (RV/BW), and the ratio of RV weight to left ventricular plus septal weight (RV/LV + S), and significantly attenuated the hypoxia-induced increase in medial wall thickness of peripheral pulmonary arteries. Furthermore, there were no significant differences in the degree of amelioration in RV systolic pressure, RV/BW, RV/LV + S, and percentage of wall thickness of peripheral pulmonary arteries between AAV1-hPGIS and AAV2-hPGIS administrations. In conclusion, we revealed that type 1 and type 2 AAV are equally effective for the treatment of PAH in a hypoxia-induced mouse model. Gene-transfer therapy using AAV expressing hPGIS is, therefore, a potential therapeutic breakthrough for PAH.

KW - adeno-associated virus

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