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

Area of Science:

• Cardiovascular Research
• Pulmonary Medicine
• Pharmacology

Background:

• Matrix metalloproteinases (MMPs) influence vascular contractility and may impact acute pulmonary embolism (APE)-induced pulmonary hypertension.
• Investigating MMP inhibitors like doxycycline offers a potential therapeutic avenue for APE.

Purpose of the Study:

• To evaluate the therapeutic effects of doxycycline, an MMP inhibitor, administered after inducing APE in a canine model.
• To determine the role of MMP-9 in the development of APE-induced pulmonary hypertension.

Main Methods:

• Anesthetized dogs underwent sham operations or APE induction via microsphere injection.
• Embolized dogs received either saline or doxycycline (10 mg/kg IV) at 5 or 30 minutes post-APE.
• Hemodynamic parameters (MPAP, PVRI, cardiac index) were monitored, and plasma MMP-2 and MMP-9 levels were analyzed using gelatin zymography.

Main Results:

• APE significantly increased mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance index (PVRI) in the saline-treated group.
• Doxycycline administration attenuated these increases, significantly reducing MPAP and PVRI in both early (5 min) and delayed (30 min) treatment groups.
• Elevated plasma MMP-9 levels were observed only in the embolized group, while MMP-2 levels remained unchanged.

Conclusions:

• Doxycycline effectively attenuates APE-induced pulmonary hypertension in a canine model.
• The findings strongly indicate that MMP-9 plays a significant role in the pathophysiology of APE-induced pulmonary hypertension.
• MMP-9 represents a promising pharmacological target for managing APE.