Cardiac surgery increases the activity of matrix metalloproteinases and nitric oxide synthase in human hearts

Objectives: Heart function is variably impaired after cardiopulmonary bypas s. We hypothesized that, similar to other myocardial injury states, cardiop ulmonary bypass leads to enhanced activity of nitric oxide synthase and mat rix metalloproteinases. Methods: We obtained right atrial biopsy specimens and plasma samples at th e onset and termination of cardiopulmonary bypass in 10 patients. Biopsy sp ecimens were analyzed for nitric oxide synthase activity by using a citrull ine assay, whereas plasma and tissue were analyzed for matrix metalloprotei nase-9 and matrix metalloproteinase-2 activity by using zymography. Tissue inhibitor of metalloproteinase-4 was analyzed by means of Western blotting. The cellular expression of inducible nitric oxide, endothelial nitric oxid e synthase, matrix metalloproteinase2, and matrix metalloproteinase-9 was d etermined in right atrial biopsy samples from 3 additional patients by usin g the appropriate conjugated antibodies. Results: Nitric oxide synthase activity increased from the beginning to the end of bypass (4.46 +/- 1.07 vs 16.77 +/- 4.86 pmol citrulline/mg or prote in per minute, respectively; P =.018). Pro-matrix metalloproteinase-9 activ ity increased in hearts (199 +/- 41 vs 660 +/- 177 density units/mg protein , P =.008) and plasma (14.1 +/- 4.6 vs 52.2 +/- 5.9 density units/mg protei n; P =.008). Pro-matrix metalloproteinase-2 activity increased in the heart (201 +/- 23 vs 310 +/- 35 density units/mg protein, P <.05) but not in pla sma. Tissue inhibitor of metalloproteinase-4 expression in the heart decrea sed (1574 +/- 280 vs 864 +/- 153 density units, P =.014). Conclusions: Cardiopulmonary bypass activates enzymes mediating acute infla mmation and organ injury (ie, nitric oxide synthase, matrix metalloproteina se-9, and matrix metalloproteinase-2). Decreased tissue inhibitor of metall oproteinase-4 expression allows relatively unopposed increases in matrix me talloproteinase tissue activity. We postulate that these changes play a rol e in the pathogenesis of heart dysfunction after bypass surgery.