Camp Teresa M, Tyagi Sam C, Aru Giorgio M, Hayden Melvin R, Mehta Jay L, Tyagi Suresh C
Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202, USA.
J Heart Lung Transplant. 2004 Jun;23(6):729-36. doi: 10.1016/j.healun.2003.06.005.
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.
Doxycycline ameliorates endothelial dysfunction, in part, by inhibiting MMP activity.
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.
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.
Results suggest a protective action of doxycycline in the ischemic heart, possibly because of additional pharmacologic actions such as metalloproteinase inhibition.
尽管心肌梗死后基质金属蛋白酶（MMP）活性增加，但内皮功能却下降。抗生素强力霉素在体外可抑制MMP活性。强力霉素介导的MMP抑制在内皮功能中的作用尚不清楚。
强力霉素部分通过抑制MMP活性改善内皮功能障碍。
通过结扎左前降支使Sprague-Dawley雄性大鼠发生心肌梗死。另一组大鼠进行假手术。在手术前2天给两组大鼠饮用含强力霉素（0.67 mg/ml）的水：假手术组进行假手术并接受强力霉素治疗，心肌梗死组进行心肌梗死并接受强力霉素治疗（每组n = 6）。4周后，将大鼠麻醉，从梗死缺血（I）、非梗死近梗死（NI）以及接受和未接受强力霉素治疗的假手术心脏中制备左心室环。
通过酶谱法测定，与其他组相比，I和NI心脏中的MMP-2活性显著增加，且仅在I心脏中观察到MMP-9活性选择性增加（p < 0.05）。通过蛋白质印迹分析测定，金属蛋白酶的心脏抑制剂仅在I心脏中降低（与其他组相比p < 0.05），而强力霉素治疗可逆转这种降低。I组中环对乙酰胆碱的收缩反应减弱，提示一氧化氮介导的功能障碍，而强力霉素可逆转此现象。I心脏中对硝普钠的反应减弱，强力霉素可改善此现象，提示心肌细胞功能障碍。缓激肽可使假手术心脏和NI心脏的环舒张，但使I心脏的环产生反常收缩。强力霉素治疗可逆转反常收缩。
结果提示强力霉素对缺血心脏具有保护作用，可能是由于其诸如抑制金属蛋白酶等额外的药理作用。
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