Therapeutic efficacy of AAV1.SERCA2a in monocrotaline-induced pulmonary arterial hypertension.

Abstract

BACKGROUND:

Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) and alterations in Ca(2+) homeostasis in vascular smooth muscle cells that stimulate 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 model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells 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 in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline 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 in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying β-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying β-galactosidase 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.

• Authors: Lahouaria Hadri, Razmig G Kratlian, Ludovic Benard, Bradley A Maron, Peter Dorfmüller, Dennis Ladage, Christophe Guignabert, Kiyotake Ishikawa, Jaume Aguero, Borja Ibanez, Irene C Turnbull, Erik Kohlbrenner, Lifan Liang, Krisztina Zsebo, Marc Humbert, Jean-Sébastien Hulot, Yoshiaki Kawase, Roger J Hajjar, Jane A Leopold
• Journal: Circulation (Circulation) Vol. 128 Issue 5 Pg. 512-23 (Jul 30 2013) ISSN: 1524-4539 [Electronic] United States
• PMID: 23804254 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Monocrotaline
• Sarcoplasmic Reticulum Calcium-Transporting ATPases
• ATP2A2 protein, human

Topics

• Animals
• Cells, Cultured
• Disease Models, Animal
• Down-Regulation (drug effects, genetics)
• Familial Primary Pulmonary Hypertension
• Gene Transfer Techniques
• HEK293 Cells
• Heart Ventricles (metabolism, pathology)
• Humans
• Hypertension, Pulmonary (chemically induced, enzymology, therapy)
• Male
• Monocrotaline (toxicity)
• Muscle, Smooth, Vascular (drug effects, metabolism)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Sarcoplasmic Reticulum Calcium-Transporting ATPases (biosynthesis, genetics, therapeutic use)
• Treatment Outcome