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 Ca2+-ATPase 2a (SERCA2a) and alterations in Ca2+ 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.

Attenuation of Monocrotaline-Induced Pulmonary Hypertension by Luminal Adeno-Associated Virus Serotype 9 Gene Transfer of Prostacyclin Synthase

“…4C and D), which are consistent with data from Hadri et al (2013) (Pan et al, 1993). Despite these strain differences, the data presented from our study compare favorably to the data from the intramuscular injection of AAV1 and AAV2-hPGIS vectors and luminal airway aerosol administration of AAV-SERCA2 vectors in a prevention of MCT-induced PAH model (Ito et al, 2007;Kawakami et al, 2007;Hadri et al, 2013;Kataoka et al, 2013).…”

“…Prior studies of intramuscular injection of AAV1 and AAV2-hPGIS vectors also used a prevention model approach (Ito et al, 2007;Kawakami et al, 2007;Kataoka et al, 2013). In contrast, Hadri et al (2013) administered an AAV1-SER-CA2 vector by luminal airway aerosol administration with a Penn Century Device in both prevention and established MCT-PAH models with similar results. Unlike our study, Hadri and associates performed their studies in older male Sprague Dawley rats (350 g), whereas our studies were performed in younger females and males (150 g).…”

“…Delivery of adeno-associated virus serotype 1 (AAV1)-and AAV2-hPGIS vectors by intramuscular injection has been shown to attenuate monocrotaline (MCT)-induced and chronic hypoxic PAH in rodents (Ito et al, 2007;Kawakami et al, 2007;Kataoka et al, 2013). Recently, attenuation of established MCT-induced PAH by aerosolized airway luminal delivery of AAV1-SERCA2 with a Penn Century Device has been reported (Hadri et al, 2013).…”

Advances in Therapeutic Interventions for Patients With Pulmonary Arterial Hypertension

“…147 More recently, SERCA2a protein expression was found to be downregulated in IPAH pulmonary arteries, and gene transfer of SERCA2a using aerosolized adeno-associated virus serotype 1 reversed pulmonary artery remodeling in monocrotaline-treated rats. 150 Manipulation of Ca 2+ signaling pathways (other than the currently used voltage-dependent Ca 2+ channels blockers) is another potential therapeutic target in PAH.…”

Advancing knowledge of right ventricular pathophysiology in chronic pressure overload: Insights from experimental studies

“…The use of multikinase inhibitors in RV remodelling has been applied only in experimental models of compensated RV hypertrophy, and not yet in RVF [73]. Gene transfer of sarcoplasmic endoplasmic reticular calcium adenosine triphosphatase 2a (SERCA-2a) has recently been demonstrated to have in vivo therapeutic efficacy in a rodent model of chronic PH, as illustrated by a marked decrease in pulmonary haemodynamics and myocardial hypertrophy and fibrosis [74]. Other non-pharmacological approaches have been suggested to target the failing RV, including myocardial bioengineering, cardiac resynchronization and RV mechanical support.…”