A role for matrix metalloproteinase-9 in the hemodynamic changes following acute pulmonary embolism

Background: Matrix metalloproteinases (MMPs) modulate vascular contractility and may affect acute pulmonary embolism (APE)-induced pulmonary hypertension. We examined the effects of the administration of doxycycline (a MMP inhibitor) following APE in anesthetized dogs. Methods: Sham operated dogs (N = 5) received only saline. APE was induced by intravenous injections of microspheres in amounts to increase mean pulmonary artery pressure (MPAP) by 20 mm Hg, and embolized dogs received saline (Emb group, N = 8), or doxycycline (10 mg/kg, i.v.) 5 or 30 min of APE (Emb + Doxy 5 and Emb + Doxy 30 groups, N = 9 and 8, respectively). Hemodynamic evaluation was performed at baseline and 5-120 after APE. Gelatin zymography of MMP-2 and MMP-9 from plasma samples was performed. Results: No significant hemodynamic changes were found in Sham animals. Embolization increased MPAP by 218 +/- 16% and the pulmonary vascular resistance index (PVRI) by 289 +/- 42% in Emb group (both P < 0.05). Doxycyline increased the cardiac index by 24 +/- 5% and reduced PVRI by 23 +/- 4% 120 min of APE in Doxy 30+Emb group. In addition, doxycyline reduced MPAP and PVRI 30 min after APE with maximum effects seen 120 min after APE (25 4% decrease in MPAP and 33 +/- 6% decrease in PVRI; both P < 0.05) in Doxy+5 group. Plasma pro-MMP-9 and MMP-9 levels increased only in Emb group and MMP-2 remained unaltered. Conclusions: Our study shows that doxycycline attenuates APE-induced pulmonary hypertension, and indicates that MMP-9 has a role in APE-induced pulmonary hypertension. MMP-9 may be a pharmacological target in APE. (c) 2006 Elsevier Ireland Ltd. All rights reserved.