Chronic treatment with rofecoxib but not ischemic preconditioning of the myocardium ameliorates early intestinal damage following cardiac ischemia/reperfusion injury in rats

Biochem Pharmacol. 2020 Aug;178:114099. doi: 10.1016/j.bcp.2020.114099. Epub 2020 Jun 12.

Abstract

There is some recent evidence that cardiac ischemia/reperfusion (I/R) injury induces intestinal damage within days, which contributes to adverse cardiovascular outcomes after myocardial infarction. However, it is not clear whether remote gut injury has any detectable early signs, and whether different interventions aiming to reduce cardiac damage are also effective at protecting the intestine. Previously, we found that chronic treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2 (COX-2), limited myocardial infarct size to a comparable extent as cardiac ischemic preconditioning (IPC) in rats subjected to 30-min coronary artery occlusion and 120-min reperfusion. In the present study, we aimed to analyse the early intestinal alterations caused by cardiac I/R injury, with or without the above-mentioned infart size-limiting interventions. We found that cardiac I/R injury induced histological changes in the small intestine within 2 h, which were accompanied by elevated tissue level of COX-2 and showed positive correlation with the activity of matrix metalloproteinase-2 (MMP-2), but not of MMP-9 in the plasma. All these changes were prevented by rofecoxib treatment. By contrast, cardiac IPC failed to reduce intestinal injury and plasma MMP-2 activity, although it prevented the transient reduction in jejunal blood flow in response to cardiac I/R. Our results demonstrate for the first time that rapid development of intestinal damage follows cardiac I/R, and that two similarly effective infarct size-limiting interventions, rofecoxib treatment and cardiac IPC, have different impacts on cardiac I/R-induced gut injury. Furthermore, intestinal damage correlates with plasma MMP-2 activity, which may be a biomarker for its early diagnosis.

Keywords: Cyclooxygenase-2; Ischemic preconditioning; Matrix metalloproteinase; Myocardial infarction; Remote ischemia/reperfusion injury; Small intestine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Cardiotonic Agents / pharmacology*
  • Coronary Occlusion / surgery
  • Coronary Vessels / surgery
  • Cyclooxygenase 2 / blood
  • Cyclooxygenase 2 / genetics*
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Disease Models, Animal
  • Drug Administration Schedule
  • Gene Expression
  • Intestine, Small / drug effects*
  • Intestine, Small / pathology
  • Ischemic Preconditioning / methods
  • Lactones / pharmacology*
  • Male
  • Matrix Metalloproteinase 2 / blood
  • Matrix Metalloproteinase 2 / genetics*
  • Matrix Metalloproteinase 9 / blood
  • Matrix Metalloproteinase 9 / genetics
  • Myocardial Reperfusion Injury / blood
  • Myocardial Reperfusion Injury / diagnosis
  • Myocardial Reperfusion Injury / genetics
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium / enzymology
  • Myocardium / pathology
  • Rats
  • Rats, Wistar
  • Sulfones / pharmacology*

Substances

  • Biomarkers
  • Cardiotonic Agents
  • Cyclooxygenase 2 Inhibitors
  • Lactones
  • Sulfones
  • rofecoxib
  • Cyclooxygenase 2
  • Ptgs2 protein, rat
  • Matrix Metalloproteinase 2
  • Mmp2 protein, rat
  • Matrix Metalloproteinase 9
  • Mmp9 protein, rat