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
| Autor: | Keiichi Fukuda, Tadashi Tanabe, Yuichi Tamura, Takashi Kawakami, Masaharu Kataoka, Hideaki Yoshino, Toru Satoh |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Systole Hypertension Pulmonary Prostaglandin Pulmonary Artery Pharmacology medicine.disease_cause Muscle hypertrophy Mice chemistry.chemical_compound Cytochrome P-450 Enzyme System Animals Humans Medicine Familial Primary Pulmonary Hypertension Pharmacology (medical) Adeno-associated virus Hypertrophy Right Ventricular business.industry Genetic Therapy Dependovirus Hypoxia (medical) Virology Peripheral Intramolecular Oxidoreductases Mice Inbred C57BL Blood pressure chemistry Ventricular pressure medicine.symptom Cardiology and Cardiovascular Medicine business |
| Zdroj: | Journal of Cardiovascular Pharmacology and Therapeutics. 18:54-59 |
| ISSN: | 1940-4034 1074-2484 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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