Abstract 18398: Prevention of Pulmonary Hypertension with Intra-tracheal Delivery of AAV1.SERCA2A
Background: Pulmonary arterial hypertension (PAH) is a life-threatening disease, with currently no satisfactory established treatments. Gene transfer using adeno-associated virus (AAV) is well known for its safety and ability to express exogenous genes for prolonged periods. SERCA2a over expression was shown to prevent remodeling and proliferation of vascular smooth muscle cells (VSMC) and to increase vasodilating NO production by eNOS. Thus, we hypothesized that SERCA2a over expression may prevent the adverse remodeling of VSMCs in the pulmonary arterial tree.
Methods: We induced pulmonary hypertension in male rats by subcutaneous injection of monocrotaline (MCT) at a dose of 50mg/kg. At the same time, we delivered either adeno-associated vector type 1 carrying SERCA2a controlled by the CMV promoter, AAV1.SERCA2a (10E11 particles), or AAV1.GFP via a catheter placed within the tracheal tube into the lungs while the animal was breathing spontaneously. We determined the effects of SERCA2a gene transfer on pulmonary artery pressure and cardiac function one month later using a pressure-volume measurement system.
Results: Control and treatment groups (n=8) were comparable in their bodyweight at baseline. Efficient transfection was confirmed with immunhistochemistry. Catheterization of the pulmonary artery and right ventricle showed significantly lower systolic and diastolic pressures in treated animals (PAsys: 36.6 ± 3.6 vs. 45.8 ± 4.4 mmHg, P < 0.05) as well as reduced pulmonary vascular resistance (0.44 ± 0.05 vs. 0.63 ± 0.01 mmHg/mL/min, P < 0.05). Left ventricular pressures remained unchanged (LVsys: 94.7 ± 6.0 vs. 101.4 ± 5.5 mmHg) as well as dP/dtMax (5775 ± 589.2 vs.6404 ± 818.7 mmHg/s). Right ventricular weight at sacrifice at one month was significantly reduced in the SERCA2a group (0.32 ± 0.02 vs. 0.39 ± 0.03 g, P < 0.05). The weight of the left ventricle adjusted to bodyweight did not differ among groups.
Conclusions: In summary, transfection of the lung with AAV1.SERCA2a via an intra-tracheal route was efficient and safe. Intra-tracheal application of AAV vectors carrying SERCA2a represents a promising and an innovative strategy for the treatment of pulmonary hypertension.
- © 2010 by American Heart Association, Inc.