ABSTRACT
BACKGROUND: Although matrix metalloproteinase (MMP) activity increases, endothelial function decreases after myocardial infarction (MI). The antibiotic doxycycline inhibits MMP activity in vitro. The role of doxycycline-mediated MMP inhibition in endothelial function is unclear. HYPOTHESIS: Doxycycline ameliorates endothelial dysfunction, in part, by inhibiting MMP activity. METHODS: We subjected Sprague-Dawley male rats to MI by ligating the left anterior descending arteries. We subjected another group of rats to sham surgery. We administered doxycycline in drinking water (0.67 mg/ml) to both groups 2 days before surgery: the sham group underwent sham surgery and received doxycycline therapy, and the MI group underwent MI and received doxycycline therapy (n = 6 in each group). After 4 weeks, we anesthetized rats and prepared left ventricular rings from infarcted-ischemic (I), non-infarcted near-infarcted (NI), and sham surgery hearts with and without doxycycline treatment. RESULTS: The MMP-2 activity increased significantly in I and NI hearts, and we observed a selective increase in MMP-9 activity only in I hearts, when compared with other groups (p < 0.05), measured by zymography. Cardiac inhibitor of metalloproteinase decreased only in I hearts (p < 0.05 vs other groups), measured by Western analysis, and doxycycline treatment reversed this decrease. Contractile response of rings to acetylcholine was attenuated in the I group, suggesting nitric oxide-mediated dysfunction, and was reversed by doxycycline. The response to nitroprusside was attenuated in I hearts and ameliorated by doxycycline, suggesting cardiomyocyte dysfunction. Bradykinin induced relaxation in rings from sham surgery hearts and from NI hearts, but induced paradoxic contraction in rings from I hearts. Treatment with doxycycline reversed the paradoxic contraction. CONCLUSION: Results suggest a protective action of doxycycline in the ischemic heart, possibly because of additional pharmacologic actions such as metalloproteinase inhibition.
Subject(s)
Cardiotonic Agents/pharmacology , Doxycycline/pharmacology , Endocardium/drug effects , Matrix Metalloproteinase 9/metabolism , Myocardial Infarction/metabolism , Ventricular Remodeling/drug effects , Animals , Endocardium/physiopathology , Hydroxyproline/metabolism , Matrix Metalloproteinase 2/drug effects , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/drug effects , Matrix Metalloproteinase Inhibitors , Rats , Rats, Sprague-Dawley , Tissue Inhibitor of Metalloproteinases/drug effects , Tissue Inhibitor of Metalloproteinases/metabolism , Tissue Inhibitor of Metalloproteinase-4ABSTRACT
Endurance exercise provides cardioprotection against ischemia-reperfusion-induced myocardial stunning and infarction. A recent study demonstrates that an exercise-induced increase in myocardial manganese superoxide dismutase (MnSOD) activity is essential to protect the heart against infarction. It is unknown if an elevation in cardiac MnSOD is also a prerequisite to achieve exercise-induced protection against myocardial stunning. Therefore, this study determined if an exercise-induced increase in myocardial MnSOD activity is a requirement to achieve protection against myocardial stunning. Adult male rats remained sedentary or performed successive bouts of endurance exercise. Hearts were exposed to 25 min of global ischemia followed by reperfusion in an isolated working heart preparation. Postischemic recovery of cardiac external work during reperfusion was significantly higher (84 +/- 3 vs. 67 +/- 4%) in exercised animals compared with sedentary controls. Furthermore, prevention of exercise-induced expression of myocardial MnSOD via antisense oligonucleotides did not retard this exercise-induced protection against myocardial stunning. These data demonstrate that exercise-induced increases in cardiac MnSOD activity are not essential to achieve exercise-mediated protection against myocardial stunning. Therefore, we conclude that different mediators are responsible for exercise-induced cardioprotection against myocardial stunning and infarction.
