Role of oxidative stress versus lipids in monocrotaline-induced pulmonary hypertension and right heart failure

Abstract

Pulmonary hypertension (PH) is a global health issue with a prevalence of 10% in ages >65 years. Right heart failure (RHF) is the main cause of death in PH. We have previously shown that monocrotaline (MCT)-induced PH and RHF are due to an increase in oxidative stress. In this study, probucol (PROB), a strong antioxidant with a lipid-lowering property, versus lovastatin (LOV), a strong lipid-lowering drug with some antioxidant effects, were evaluated for their effects on the MCT-induced RHF. Rats were treated (I.P.) with PROB (10 mg/kg ×12) or LOV (4 mg/kg ×12), daily 6 days before and 6 days after a single MCT injection (60 mg/kg). Serial echocardiography was performed and at 4-week post-MCT, lung wet-to-dry weight, hemodynamics, RV glutathione peroxidase (GSHPx), superoxide dismutase (SOD), catalase, lipid peroxidation, and myocardial as well as plasma lipids were examined. MCT increased RV systolic and diastolic pressures, wall thickness, RV end diastolic diameter, mortality, and decreased ejection fraction as well as pulmonary artery acceleration time. These changes were mitigated by PROB while LOV had no effect. Furthermore, PROB prevented lipid peroxidation, lowered lipids, and increased GSHPx and SOD in RV myocardium. LOV did decrease the lipids but had no effect on antioxidants and lipid peroxidation. A reduction in oxidative stress and not the lipid-lowering effect of PROB may explain the prevention of MCT-induced PH, RHF, and mortality. Thus targeting of oxidative stress as an adjuvant therapy is suggested.

Keywords: antioxidants; oxidative stress; pulmonary hypertension; right heart failure.

FIGURE 1

Effect of probucol (PROB) and lovastatin (LOV) on monocrotaline (MCT)‐induced changes in right ventricle systolic pressure (RVSP) and right ventricular diastolic pressure (RVDP) in rats at 4‐week post‐MCT treatment. Data are mean ± SEM of 9–12 animals. *Significantly different (p < 0.05) from the respective controls (CONT); ^†Significantly different (p < 0.05) from the respective values in the MCT group

FIGURE 2

Effect of probucol (PROB) and lovastatin (LOV) on monocrotaline (MCT)‐induced changes in pulmonary artery acceleration time (PAAT) in rats at 4‐week post‐MCT treatment. Acceleration time was measured from the time of onset of systolic flow to peak pulmonary outflow. Data are mean ± SEM of 9–12 animals. ^*Significantly different (p < 0.05) from the control (CONT) group; ^†Significantly different (p < 0.05) from the MCT group

FIGURE 3

Effect of probucol (PROB) and lovastatin (LOV) on monocrotaline (MCT)‐induced changes in lipid peroxidation assessed by thiobarbituric acid‐reactive substances (TBARS) in rats at 4‐week post‐MCT treatment. Data are mean ± SEM of 5–6 animals. ^*Significantly different (p < 0.05) from the control (CONT) group; ^†Significantly different (p < 0.05) from the MCT and LOV + MCT groups