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Matrix metalloproteinase activities are altered in the heart and plasma during endotoxemia

Lalu, Manoj M. PhD; Csont, Tamás MD, PhD; Schulz, Richard PhD

doi: 10.1097/01.CCM.0000127778.16609.EC
Laboratory Investigations

Objective: To investigate whether myocardial and plasma matrix metalloproteinase (MMP) activities are altered during endotoxemia.

Design: Prospective randomized, animal study.

Setting: University research laboratory.

Subjects: Male Sprague-Dawley rats, 250–300 g.

Interventions: Rats were administered either bacterial lipopolysaccharide (LPS) or vehicle (pyrogen-free water). Groups of LPS-administered animals were killed at 0.5, 1, 3, 6, 12, and 24 hrs postinjection. Vehicle injected animals were killed at 6 hrs. Blood pressure was recorded before kill. Heart and plasma samples were analyzed by gelatin zymography and immunoblot.

Measurements and Main Results: Blood pressure was significantly depressed at 3–24 hrs post-LPS injection; however, overt symptoms of endotoxemia and reduction in blood pressure were most significant 6–12 hrs post-LPS. Heart samples from control rats revealed MMP-2 activity but no MMP-9 activity. MMP-2 activity was significantly depressed when overt symptoms of endotoxemia peaked at 6–12 hrs. Plasma MMP-2 activity significantly decreased 3–12 hrs after LPS injection. This loss of activity was associated with a loss of MMP-2 protein. In contrast, plasma MMP-9 activities were rapidly elevated following LPS injection, peaking between 1 and 12 hrs. MMP-9 activity correlated inversely with blood pressure.

Conclusions: Endotoxemia induced rapid changes in MMP activity in both the myocardium and plasma. An increase in circulating MMP-9 activity may contribute to endotoxemic cardiovascular dysfunction.

Departments of Pharmacology (MML, TC, RS) and Pediatrics (RS), Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada.

Supported by a grant from the Heart and Stroke Foundation of Alberta, the Northwest Territories, and Nunavut. Personnel support was provided by Alberta Heritage Foundation for Medical Research and the Canadian Institutes of Health Research (MML).

© 2004 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins