Abstract 11467: Rosvastatin Ameliorates Lung Ischemic-Reperfusion Injury via eNOS Upregulation and Inhibition of Macrophage Recruitment in Pulmonary Hypertensive Rat
Introduction: Lung ischemic-reperfusion (IR) injury during cardiac surgery with cardiopulmonary bypass is associated with postoperative morbidity and mortality, especially in patients with pulmonary hypertension (PH). Statin, an inhibitor of HMG-CoA reductase has been demonstrated as an anti-inflammatory mediator via endothelial NO synthase (eNOS) for IR injury in normotensive lung. A role of statin on lung IR injury in PH with impaired endothelial function has not been defined yet. The aims of this study are to investigate whether statin can exert a protective effect on the IR injury in PH and to elucidate some mechanisms of statin’s action to mediate lung IR injury in PH.
Methods: Male Sprague-Dawley monocrotaline-treated rats were divided into 4 groups (n=8-9): Sham, IR-saline (control), IR-Rosvastatin (IR+R), and IR-Rosvastatin + Mevalonate. Lung ischemia was induced by occlusion of the left pulmonary artery for an hour, followed by reperfusion for 4 hours. Rosvastatin (2mg/kg) was injected intraperitoneally 18 hours before ischemia. Mevalonate (1mg/kg) was injected intraperitoneally just before reperfusion. Arterial blood was collected at the end of reperfusion to evaluate P/F ratio. Left lung tissue was submitted to measure wet to dry (W/D) weight ratio and the expression of eNOS and phospho-eNOS by western blotting. Macrophage recruitment was assessed by CD68 immunostaining.
Results: Right ventricular systolic pressure before ischemia (average 45.2±2.8 mmHg) was not significantly different among all the groups. Rosvastatin significantly improved P/F ratio, W/D ratio and recruitment of macrophage (IR+R vs control: 442±38 vs 272±42, 4.6±0.3 vs 5.7±0.2, 3.4±1.1 vs 10.5±1.8 /field; P<0.03, respectively). These beneficial effects were blunted by adding mevalonate which is downstream metabolite of HMG-CoA. The expression of eNOS was augmented by Rosvastatin to the level of sham group, which was diminished by mevalonate to the level of control. On the other hand, no significant difference was observed in terms of phospho-eNOS/eNOS between the groups.
Conclusions: Single dose Rosvastatin ameliorates lung IR injury even in PH by way of two anti-inflammatory synergic mechanisms, upregulation of eNOS and inhibition of macrophage recruitment.
- © 2013 by American Heart Association, Inc.