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

Roberto Bolli, Ken Shinmura, Xian Liang Tang, Eitaro Kodani, Yu Ting Xuan, Yiru Guo, Buddhadeb Dawn

Research output: Contribution to journalArticle

201 Citations (Scopus)

Abstract

More than 10 years after its discovery, the function of cyclooxygenase-2 (COX-2) in the cardiovascular system remains largely an enigma. Many scholars have assumed that the allegedly detrimental effects of COX-2 in other systems (e.g. proinflammatory actions and tumorigenesis) signify a detrimental role of this protein in cardiovascular homeostasis as well. This view, however, is ill-founded. Recent studies have demonstrated that ischemic preconditioning (PC) upregulates the expression and activity of COX-2 in the heart, and that this increase in COX-2 activity mediates the protective effects of the late phase of PC against both myocardial stunning and myocardial infarction. An obligatory role of COX-2 has been observed in the setting of late PC induced not only by ischemia but also by δ-opioid agonists and physical exercise, supporting the view that the recruitment of this protein is a central mechanism whereby the heart protects itself from ischemia. The beneficial actions of COX-2 appear to be mediated by the synthesis of PGE2 and/or PGI2. Since inhibition of iNOS in preconditioned myocardium blocks COX-2 activity whereas inhibition of COX-2 does not affect iNOS activity, COX-2 appears to be downstream of iNOS in the protective pathway of late PC. The results of these studies challenge the widely accepted paradigm that views COX-2 activity as detrimental. The discovery that COX-2 plays an indispensable role in the anti-stunning and anti-infarct effects of late PC demonstrates that the recruitment of this protein is a fundamental mechanism whereby the heart adapts to stress, thereby revealing a novel, hitherto unappreciated cardioprotective function of COX-2. From a practical standpoint, the recognition that COX-2 is an obligatory co-mediator (together with iNOS) of the protection afforded by late PC has implications for the clinical use of COX-2 selective inhibitors as well as nonselective COX inhibitors. For example, the possibility that inhibition of COX-2 activity may augment myocardial cell death by obliterating the innate defensive response of the heart against ischemia/reperfusion injury needs to be considered and is the object of much current debate. Furthermore, the concept that the COX-2 byproducts, PGE2 and/or PGI2, play a necessary role in late PC provides a basis for novel therapeutic strategies designed to enhance the biosynthesis of these cytoprotective prostanoids in the ischemic myocardium. From a conceptual standpoint, the COX-2 hypothesis of late PC expands our understanding of the function of this enzyme in the cardiovascular system and impels a critical reassessment of current thinking regarding the biologic significance of COX-2.

Original languageEnglish
Pages (from-to)506-519
Number of pages14
JournalCardiovascular Research
Volume55
Issue number3
DOIs
Publication statusPublished - 2002

Fingerprint

Cyclooxygenase 2
Reperfusion Injury
Proteins
Epoprostenol
Cardiovascular System
Dinoprostone
Myocardium
Ischemia
Myocardial Stunning
Ischemic Preconditioning
Cyclooxygenase Inhibitors
Cyclooxygenase 2 Inhibitors
Opioid Analgesics
Prostaglandins

Keywords

  • Ischemia
  • Nitric oxide
  • Preconditioning
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

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. / Bolli, Roberto; Shinmura, Ken; Tang, Xian Liang; Kodani, Eitaro; Xuan, Yu Ting; Guo, Yiru; Dawn, Buddhadeb.

In: Cardiovascular Research, Vol. 55, No. 3, 2002, p. 506-519.

Research output: Contribution to journalArticle

Bolli, Roberto ; Shinmura, Ken ; Tang, Xian Liang ; Kodani, Eitaro ; Xuan, Yu Ting ; Guo, Yiru ; Dawn, Buddhadeb. / 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. In: Cardiovascular Research. 2002 ; Vol. 55, No. 3. pp. 506-519.
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