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.

Hemodynamic benefits of matrix metalloproteinase-9 inhibition by doxycycline during experimental acute pulmonary embolism.

The authors examined whether acute pulmonary embolism (APE) increases lung matrix metalloproteinase (MMP)-2 and MMP-9 activities and whether inhibition of MMPs with doxycycline attenuates the hemodynamic changes associated with APE. Anesthetized male Wistar rats were monitored for mean arterial blood pressure (MAP) and heart rate (HR). Rats in the control group (n = 5) received only saline IV; rats in the embolism (Emb) group (n = 8) received saline IV followed 10 minutes later by an injection of Sephadex microspheres (9 mg/kg) IV; rats in the doxycycline (Doxy) group (n = 4) received only doxycycline (30 mg/kg) IV, followed 10 minutes later by an injection of saline IV; rats in the Doxy + Emb group (n = 8) received the same dose of doxycycline followed 10 minutes later by the same amount of microspheres described above. Lung samples were homogenized and assayed by SDS-polyacrilamide gel electrophoresis gelatin zymography to evaluate lung MMP-2 and MMP-9 activities. Saline or doxycycline produced no significant changes in MAP, HR, and in MMP-2 and MMP-9 activities. Conversely, lung embolization significantly reduced MAP by > 32 mm Hg and HR by > 90 bpm for more than 60 minutes, and increased MMP-9 activity by 43% (all p < 0.05). No significant differences were observed in MMP-2 activity. However, lung embolization produced only transient hypotension in rats pretreated with doxycycline. In this group, MAP returned to baseline values 5 to 10 minutes after embolization. In addition, pretreatment with doxycycline blunted the increase in lung MMP-9 activity after lung embolization (p < 0.05). This study demonstrates for the first time that MMP-9 inhibition with doxycycline attenuates APE-induced hemodynamic changes in the animal model examined. These findings indicate that MMP-9 activation plays a role in the pathophysiology of APE and suggest that pharmacologic strategies targeting specific MMPs with selective inhibitors may prevent the detrimental acute hemodynamic consequences of APE.