Therapeutic Efficacy of AAV1.SERCA2a in Monocrotaline-Induced Pulmonary Arterial Hypertension
Background—Pulmonary artery hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells (PASMC) leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and alterations in Ca2+ homeostasis in vascular smooth muscle cells that stimulates proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH.
Methods and Results—SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline (MCT) model of PAH compared to controls. In human PASMC in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells (PAEC) in vitro increased endothelial nitric oxide synthase expression and activation. In MCT rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy and fibrosis compared to MCT-PAH rats treated with a control AAV1 carrying β-Galactosidase (AAV1.βGal) or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of MCT administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling compared with rats administered AAV1.βGal or saline.
Conclusions—Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.
- right ventricular systolic pressure
- Adeno-associated virus
- nitric oxide synthase
- animal model of human disease remodeling
- pulmonary hypertension
- pulmonary artery
- calcium signaling
- cardiovascular research
- Received January 24, 2013.
- Revision received June 5, 2013.
- Accepted June 13, 2013.