Protective effects of atorvastatin in rat models of acute pulmonary embolism: Involvement of matrix metalloproteinase-9

Objective: Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of acute pulmonary embolism (APE)induced pulmonary hypertension. Here, we evaluate the effects of atorvastatin pretreatment on APE-induced pulmonary hypertension, 24-hr mortality rate, and changes in plasma and lung MMP-2 and MMP-9 activities. Design: Controlled animal study. Setting., University research laboratory. Subjects: Male Wistar rats. Interventions. Rats received atorvastatin (30 mg/kg/day orally) or tap water for 2 wks. In study 1, we examined whether atorvastatin affected APE-induced pulmonary hypertension by using a rat isolated lung perfusion model of APE. In study 2, we examined whether atorvastatin affects the survival rate after APE, which was induced by rapid intravenous injection of 14 mg/kg of a suspension of microspheres (or saline) into the tail vein. Measurements and Main Results., Plasma nitrite/nitrate concentrations were measured by chemiluminescence. Pretreatment with atorvastatin was associated with 49% higher nitrite/nitrate levels compared with controls (p <.05). In study 1, whereas APE increased mean pulmonary artery pressure (MPAP) by 13.0 +/- 1.6 mm Hg in perfused lungs isolated from rats pretreated with water, pretreatment with atorvastatin attenuated by 27% the increases in MPAP after APE. In study 2, pretreatment with atorvastatin was associated with a significant increase in 24-hr survival rate after APE, which was 48% in embolized rats pretreated with water and 64% in rats pretreated with atorvastatin (p <.05). Gelatin zymography of lung and plasma MMP-2 and MMP-9 was performed. Lungs and plasma from embolized rats showed higher levels of both pro- and activated forms of MMP-9 compared with those from nonembolized animals (all p <.05). However, pretreatment with atorvastatin attenuated by 32% the increases in lung-activated MMP-9 levels after APE (p <.05). Conclusions: These results suggest that pretreatment with atorvastatin attenuates APE-induced pulmonary hypertension and increases 24-hr survival rate by mechanisms that result in attenuated increases in lung activated MMP-9 after APE.