Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Abbate A, Santini D, Biondi-Zoccai GG, Scarpa S, Vasaturo F, Liuzzo G, Bussani R, Silvestri F, Baldi F, Crea F, Biasucci LM, Baldi A (2004) Cyclo-oxygenase-2 (COX-2) expression at the site of recent myocardial infarction: friend or foe? Heart 90:440–443. https://doi.org/10.1136/hrt.2003.010280

    Article  CAS  Google Scholar 

  2. Bennett WR, Yawn DH, Migliore PJ, Young JB, Pratt CM, Raizner AE, Roberts R, Bolli R (1987) Activation of the complement system by recombinant tissue plasminogen activator. J Am Coll Cardiol 10:627–632. https://doi.org/10.1016/S0735-1097(87)80206-1

    Article  CAS  Google Scholar 

  3. Bolli R, Shinmura K, Tang XL, Kodani E, Xuan YT, Guo Y, Dawn B (2002) Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning. Cardiovasc Res 55:506–519. https://doi.org/10.1016/S0008-6363(02)00414-5

    Article  CAS  Google Scholar 

  4. Botker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femmino S, Garcia-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhauser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schluter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39. https://doi.org/10.1007/s00395-018-0696-8

    Article  Google Scholar 

  5. Dawn B, Guo Y, Rezazadeh A, Huang Y, Stein AB, Hunt G, Tiwari S, Varma J, Gu Y, Prabhu SD, Kajstura J, Anversa P, Ildstad ST, Bolli R (2006) Postinfarct cytokine therapy regenerates cardiac tissue and improves left ventricular function. Circ Res 98:1098–1105. https://doi.org/10.1161/01.RES.0000218454.76784.66

    Article  CAS  Google Scholar 

  6. Futaki N, Takahashi S, Yokoyama M, Arai I, Higuchi S, Otomo S (1994) NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro. Prostaglandins 47:55–59. https://doi.org/10.1016/0090-6980(94)90074-4

    Article  CAS  Google Scholar 

  7. Gres P, Schulz R, Jansen J, Umschlag C, Heusch G (2002) Involvement of endogenous prostaglandins in ischemic preconditioning in pigs. Cardiovasc Res 55:626–632. https://doi.org/10.1016/s0008-6363(01)00505-3

    Article  CAS  Google Scholar 

  8. Guo Y, Bao W, Wu WJ, Shinmura K, Tang XL, Bolli R (2000) Evidence for an essential role of cyclooxygenase-2 as a mediator of the late phase of ischemic preconditioning in mice. Basic Res Cardiol 95:479–484. https://doi.org/10.1007/s003950070

    Article  CAS  Google Scholar 

  9. Guo Y, Flaherty MP, Wu WJ, Tan W, Zhu X, Li Q, Bolli R (2012) Genetic background, gender, age, body temperature, and arterial blood pH have a major impact on myocardial infarct size in the mouse and need to be carefully measured and/or taken into account: results of a comprehensive analysis of determinants of infarct size in 1,074 mice. Basic Res Cardiol 107:288. https://doi.org/10.1007/s00395-012-0288-y

    Article  Google Scholar 

  10. Guo Y, Jones WK, Xuan YT, Tang XL, Bao W, Wu WJ, Han H, Laubach VE, Ping P, Yang Z, Qiu Y, Bolli R (1999) The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene. Proc Natl Acad Sci USA 96:11507–11512. https://doi.org/10.1073/pnas.96.20.11507

    Article  CAS  Google Scholar 

  11. Guo Y, Tukaye DN, Wu WJ, Zhu X, Book M, Tan W, Jones SP, Rokosh G, Narumiya S, Li Q, Bolli R (2012) The COX-2/PGI2 receptor axis plays an obligatory role in mediating the cardioprotection conferred by the late phase of ischemic preconditioning. PLoS One 7:e41178. https://doi.org/10.1371/journal.pone.0041178

    Article  CAS  Google Scholar 

  12. Guo Y, Wu WJ, Qiu Y, Tang XL, Yang Z, Bolli R (1998) Demonstration of an early and a late phase of ischemic preconditioning in mice. Am J Physiol 275:H1375–H1387. https://doi.org/10.1152/ajpheart.1998.275.4.H1375

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hausenloy DJ, Yellon DM (2010) The second window of preconditioning (SWOP) where are we now? Cardiovasc Drugs Thera spons Int Soc Cardiovasc Pharmacother 24:235–254. https://doi.org/10.1007/s10557-010-6237-9

    Article  Google Scholar 

  14. Inserte J, Molla B, Aguilar R, Traves PG, Barba I, Martin-Sanz P, Bosca L, Casado M, Garcia-Dorado D (2009) Constitutive COX-2 activity in cardiomyocytes confers permanent cardioprotection Constitutive COX-2 expression and cardioprotection. J Mol Cell Cardiol 46:160–168. https://doi.org/10.1016/j.yjmcc.2008.11.011

    Article  CAS  Google Scholar 

  15. Jones SP, Tang XL, Guo Y, Steenbergen C, Lefer DJ, Kukreja RC, Kong M, Li Q, Bhushan S, Zhu X, Du J, Nong Y, Stowers HL, Kondo K, Hunt GN, Goodchild TT, Orr A, Chang CC, Ockaili R, Salloum FN, Bolli R (2015) The NHLBI-sponsored Consortium for preclinicAl assESsment of cARdioprotective therapies (CAESAR): a new paradigm for rigorous, accurate, and reproducible evaluation of putative infarct-sparing interventions in mice, rabbits, and pigs. Circ Res 116:572–586. https://doi.org/10.1161/CIRCRESAHA.116.305462

    Article  CAS  Google Scholar 

  16. Li Q, Guo Y, Ou Q, Chen N, Wu WJ, Yuan F, O’Brien E, Wang T, Luo L, Hunt GN, Zhu X, Bolli R (2011) Intracoronary administration of cardiac stem cells in mice: a new, improved technique for cell therapy in murine models. Basic Res Cardiol 106:849–864. https://doi.org/10.1007/s00395-011-0180-1

    Article  Google Scholar 

  17. Li Q, Guo Y, Ou Q, Wu WJ, Chen N, Zhu X, Tan W, Yuan F, Dawn B, Luo L, Hunt GN, Bolli R (2011) Gene transfer as a strategy to achieve permanent cardioprotection II: rAAV-mediated gene therapy with heme oxygenase-1 limits infarct size 1 year later without adverse functional consequences. Basic Res Cardiol 106:1367–1377. https://doi.org/10.1007/s00395-011-0208-6

    Article  CAS  Google Scholar 

  18. Li Q, Guo Y, Wu WJ, Ou Q, Zhu X, Tan W, Yuan F, Chen N, Dawn B, Luo L, O’Brien E, Bolli R (2011) Gene transfer as a strategy to achieve permanent cardioprotection I: rAAV-mediated gene therapy with inducible nitric oxide synthase limits infarct size 1 year later without adverse functional consequences. Basic Res Cardiol 106:1355–1366. https://doi.org/10.1007/s00395-011-0207-7

    Article  CAS  Google Scholar 

  19. Li Q, Guo Y, Xuan YT, Lowenstein CJ, Stevenson SC, Prabhu SD, Wu WJ, Zhu Y, Bolli R (2003) Gene therapy with inducible nitric oxide synthase protects against myocardial infarction via a cyclooxygenase-2-dependent mechanism. Circ Res 92:741–748. https://doi.org/10.1161/01.RES.0000065441.72685.29

    Article  CAS  Google Scholar 

  20. Li RC, Ping P, Zhang J, Wead WB, Cao X, Gao J, Zheng Y, Huang S, Han J, Bolli R (2000) PKCepsilon modulates NF-kappaB and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes. Am J Physiol Heart Circ Physiol 279:H1679–H1689. https://doi.org/10.1152/ajpheart.2000.279.4.H1679

    Article  CAS  Google Scholar 

  21. Li XY, McCay PB, Zughaib M, Jeroudi MO, Triana JF, Bolli R (1993) Demonstration of free radical generation in the “stunned” myocardium in the conscious dog and identification of major differences between conscious and open-chest dogs. J Clin Invest 92:1025–1041. https://doi.org/10.1172/JCI116608

    Article  CAS  Google Scholar 

  22. Lindsey ML, Bolli R, Canty JM Jr, Du XJ, Frangogiannis NG, Frantz S, Gourdie RG, Holmes JW, Jones SP, Kloner RA, Lefer DJ, Liao R, Murphy E, Ping P, Przyklenk K, Recchia FA, Schwartz Longacre L, Ripplinger CM, Van Eyk JE, Heusch G (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812–H838. https://doi.org/10.1152/ajpheart.00335.2017

    Article  CAS  Google Scholar 

  23. Przyklenk K, Heusch G (2003) Late preconditioning against myocardial stunning. Does aspirin close the “second window” of endogenous cardioprotection? J Am Coll Cardiol 41:1195–1197. https://doi.org/10.1016/S0735-1097(03)00087-1

    Article  Google Scholar 

  24. Sanbe A, Gulick J, Hanks MC, Liang Q, Osinska H, Robbins J (2003) Reengineering inducible cardiac-specific transgenesis with an attenuated myosin heavy chain promoter. Circ Res 92:609–616. https://doi.org/10.1161/01.RES.0000065442.64694.9F

    Article  CAS  Google Scholar 

  25. Shinmura K, Kodani E, Xuan YT, Dawn B, Tang XL, Bolli R (2003) Effect of aspirin on late preconditioning against myocardial stunning in conscious rabbits. J Am Coll Cardiol 41:1183–1194. https://doi.org/10.1016/S0735-1097(03)00086-X

    Article  CAS  Google Scholar 

  26. Shinmura K, Tang XL, Wang Y, Xuan YT, Liu SQ, Takano H, Bhatnagar A, Bolli R (2000) Cyclooxygenase-2 mediates the cardioprotective effects of the late phase of ischemic preconditioning in conscious rabbits. Proc Natl Acad Sci USA 97:10197–10202. https://doi.org/10.1073/pnas.97.18.10197

    Article  CAS  Google Scholar 

  27. Takadera T, Yumoto H, Tozuka Y, Ohyashiki T (2002) Prostaglandin E(2) induces caspase-dependent apoptosis in rat cortical cells. Neurosci Lett 317:61–64

    Article  CAS  Google Scholar 

  28. Tang XL, Qiu Y, Park SW, Sun JZ, Kalya A, Bolli R (1996) Time course of late preconditioning against myocardial stunning in conscious pigs. Circ Res 79:424–434. https://doi.org/10.1161/01.RES.79.3.424

    Article  CAS  Google Scholar 

  29. Wong SC, Fukuchi M, Melnyk P, Rodger I, Giaid A (1998) Induction of cyclooxygenase-2 and activation of nuclear factor-kappaB in myocardium of patients with congestive heart failure. Circulation 98:100–103. https://doi.org/10.1161/01.CIR.98.2.100

    Article  CAS  Google Scholar 

  30. Wu KK (1998) Cyclooxygenase-2 induction in congestive heart failure: friend or foe? Circulation 98:95–96. https://doi.org/10.1161/01.CIR.98.2.95

    Article  CAS  Google Scholar 

  31. Xuan YT, Guo Y, Zhu Y, Han H, Langenbach R, Dawn B, Bolli R (2003) Mechanism of cyclooxygenase-2 upregulation in late preconditioning. J Mol Cell Cardiol 35:525–537. https://doi.org/10.1016/S0022-2828(03)00076-2

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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

Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine and Institute of Molecular Cardiology, University of Louisville, 550 S. Jackson St., ACB, 3rd Floor, Louisville, KY, 40292, USA

    Yiru Guo, Yibing Nong, Deepali Nivas Tukaye, Gregg Rokosh, Junjie Du, Xiaoping Zhu, Michael Book, Alex Tomlin, Qianhong Li & Roberto Bolli

Authors
  1. Yiru Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yibing Nong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deepali Nivas Tukaye
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gregg Rokosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Junjie Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoping Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Michael Book
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alex Tomlin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Qianhong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Roberto Bolli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Bolli.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 112 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Guo, Y., Nong, Y., Tukaye, D.N. et al. Inducible cardiac-specific overexpression of cyclooxygenase-2 (COX-2) confers resistance to ischemia/reperfusion injury. Basic Res Cardiol 114, 32 (2019). https://doi.org/10.1007/s00395-019-0741-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-019-0741-2

Keywords

Search

Navigation