Abstract 2302: Adeno-associated Virus-mediated Prostaglandin I Synthase Gene Transfer Improved The Hypoxia-induced Pulmonary Hypertension In Mice
Background: Although prostaglandin I2 and its derivatives are clinically used for the treatment of pulmonary hypertension, continuous intravenous administration is required for the effective treatment. Prostaglandin I2 synthase (PGIS) is one of the most powerful therapeutic genes against pulmonary hypertension (PH). The purpose of this study was to investigate whether the human PGIS (hPGIS) gene transfer using adeno-associated virus (AAV) vector into the skeletal muscle was effective to the hypoxia induced-pulmonary hypertension in mice.
Methods and Results:
PH was induced in the mice subjected to hypoxic chamber (O2 10%) for 8 weeks. Right ventricular systolic pressure (RVSP) significantly increased in PH group compared with control group.
In the gene transferred group (AAV1-hPGIS), the AAV type1-hPGIS (2.0×1011 v.g./body) vector was injected into the left thigh muscle at 24 hour after exposure to hypoxia. Saline injected mice were served as control group.
After 8 weeks, hemodynamics and histological analysis was performed. AAV1-PGIS significantly decreased right ventricular systolic pressure to 26±5 mmHg compared with PH group (40±4 mmHg). Systemic blood pressure did not significantly decrease AAV-hPGIS treated group.
QT-PCR revealed that PH group increased BNP mRNA in RV by 6-fold higher, while AAV1-hPGIS group decreased to 1.3-fold compared with the control group.
Histological analysis revealed that PH group showed severe medial thickening of the pulmonary artery, and increased %wall thickness to 33.3±7.3%, while AAV1-hPGIS decreased to 17±3.6 %.
RT-PCR revealed that the hPGIS gene expression was detected only at the injected side, but not in the liver, kidney, heart, and the other organs. Histological analysis showed no pathological changes at the injected skeletal muscles.
Finally, Kaplan-Mayer analysis revealed that PH group showed 47% survival at 12 weeks wile AAV1-hPGIS group showed 73%, indicating that AAV1-hPGIS treatment significantly increased the survival of PH.
Conclusions: Our study demonstrated that the AAV1-mediaqted gene transfer of PGIS was effective to treat the hypoxia-induced pulmonary hypertension in mice, and can prolong the survival of these animals.