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Basic Research in Cardiology

, 114:32 | Cite as

Inducible cardiac-specific overexpression of cyclooxygenase-2 (COX-2) confers resistance to ischemia/reperfusion injury

  • Yiru Guo
  • Yibing Nong
  • Deepali Nivas Tukaye
  • Gregg Rokosh
  • Junjie Du
  • Xiaoping Zhu
  • Michael Book
  • Alex Tomlin
  • Qianhong Li
  • Roberto BolliEmail author
Original Contribution
  • 107 Downloads

Abstract

The role of cyclooxygenase-2 (COX-2) in cardiovascular biology remains controversial. Although COX-2 has been reported to mediate the protective actions of late preconditioning, other studies show that it is also an important mediator of inflammation, toxic shock, and apoptosis, resulting in significant dysfunction and injury in several tissues. To determine whether increased myocardial COX-2, in itself, is protective, cardiac-specific, inducible (Tet-off) COX-2 transgenic (iCOX-2 TG) mice were generated by crossbreeding α-MyHC-tTA transgenic mice (tetracycline transactivator [tTA]) with CMV/TRE-COX-2 transgenic mice. Three months after COX-2 induction, mice were subjected to a 30-min coronary occlusion and 24 h of reperfusion. Three different lines (L5, L7, and L8) of iCOX-2 TG mice were studied; in all three lines, infarct size was markedly reduced compared with WT mice: L5 TG/TG 23.4 ± 5.8 vs. WT/WT 48.5 ± 6.1% of risk region; L7 TG/TG 23.2 ± 6.2 vs. WT/WT 53.3 ± 3.6%; and L8 TG/TG 23.5 ± 2.8 vs. WT/WT 52.7 ± 4.6% (P < 0.05 for each). COX-2 inhibition with NS-398 completely abolished the cardioprotection provided by COX-2 overexpression. This study for the first time utilizes an inducible cardiac-specific COX-2 overexpression system to examine the role of this enzyme in ischemia/reperfusion injury in vivo. We demonstrate that induced cardiac-specific overexpression of COX-2 exerts a potent cardioprotective effect against myocardial infarction in mice, and that chronic COX-2 overexpression is not associated with any apparent deleterious effects. We also show that PGE2 levels are upregulated in COX-2 overexpressing cardiac tissue, confirming increased enzyme activity. Finally, we have developed a valuable genetic tool to further our understanding of the role of COX-2 in ischemia/reperfusion injury and other settings. The concept that COX-2 is chronically protective has important therapeutic implications for studies of long-term gene therapy aimed at increasing myocardial COX-2 content as well as other COX-2- based strategies.

Keywords

COX-2 Ischemia/reperfusion injury Cardioprotection Transgenic mice 

Notes

Acknowledgements

This study was supported in part by NIH Grants HL113530, HL-78825, and HL-071896-01A1.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

395_2019_741_MOESM1_ESM.pdf (112 kb)
Supplementary material 1 (PDF 112 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Division of Cardiovascular Medicine and Institute of Molecular CardiologyUniversity of LouisvilleLouisvilleUSA

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