Extracellular Superoxide Dismutase Overexpression Can Reverse the Course of Hypoxia-Induced Pulmonary Hypertension

Mohamed N Ahmed,Dhara Patel,Yinzhong Zhang,Michael Wolin,Edmund J Miller,Nahla Zaghloul,Champa Codipilly

doi:10.2119/molmed.2011.00339

Abstract

Hypoxia leads to free radical production, which has a pivotal role in the pathophysiology of pulmonary hypertension (PH). We hypothesized that treatment with extracellular superoxide dismutase (EC-SOD) could ameliorate the development of PH induced by hypoxia. In vitro studies using pulmonary microvascular endothelial cells showed that cells transfected with EC-SOD had significantly less accumulation of xanthine oxidase and reactive oxygen species than nontransfected cells after hypoxia exposure for 24 h. To study the prophylactic role of EC-SOD, adult male wild-type (WT) and transgenic (TG) mice, with lung-specific overexpression of human EC-SOD (hEC-SOD), were exposed to fraction of inspired oxygen (FiO(2)) 10% for 10 d. After exposure, right ventricular systolic pressure (RVSP), right ventricular mass (RV/S + LV), pulmonary vascular wall thickness (PVWT) and pulmonary artery contraction/relaxation were assessed. TG mice were protected against PH compared with WT mice with significantly lower RVSP (23.9 ± 1.24 versus 47.2 ± 3.4), RV/S + LV (0.287 ± 0.015 versus 0.335 ± 0.022) and vascular remodeling, indicated by PVWT (14.324 ± 1.107 versus 18.885 ± 1.529). Functional studies using pulmonary arteries isolated from mice indicated that EC-SOD prevents hypoxia-mediated attenuation of nitric oxide-induced relaxation. Therapeutic potential was assessed by exposing WT mice to FiO(2) 10% for 10 d. Half of the group was transfected with plasmid containing cDNA encoding human EC-SOD. The remaining animals were transfected with empty vector. Both groups were exposed to FiO(2) 10% for a further 10 d. Transfected mice had significantly reduced RVSP (18.97 ± 1.12 versus 41.3 ± 1.5), RV/S + LV (0.293 ± 0.012 versus 0.372 ± 0.014) and PVWT (12.51 ± 0.72 versus 18.98 ± 1.24). On the basis of these findings, we concluded that overexpression of EC-SOD prevents the development of PH and ameliorates established PH.

Highlights

Pulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle and subsequently leads to right ventricular failure
We believe that extracellular superoxide dismutase (EC-superoxide dismutase (SOD)) may be uniquely positioned to oppose PH because of its ability to catalyze the dismutation of superoxide radicals, increase nitric oxide (NO) bioavailability and decrease the inflammatory response associated with oxidative stress
In this study, we report for the first time an intervention that can reverse the PH induced by hypoxia in an adult mouse model

Summary

INTRODUCTION

Pulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle and subsequently leads to right ventricular failure. Both adults and pediatric patients with lung diseases complicated by alveolar hypoxia are at risk for developing PH, a process that significantly increases morbidity and mortality [1]. Each of the cells described above contribute to pulmonary vascular remodeling, which in turn increases resistance in the pulmonary circulation, leading to right ventricular failure [5]. In humans, increased vascular O2– production, during chronic hypoxic exposure, results in impaired nitric oxide (NO) signaling and the development of pulmonary vascular remodeling [7,11]. We believe that EC-SOD may be uniquely positioned to oppose PH because of its ability to catalyze the dismutation of superoxide radicals, increase NO bioavailability and decrease the inflammatory response associated with oxidative stress

MATERIALS AND METHODS

RESULTS

Findings

DISCUSSION