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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.