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Cited by 270Cardiac Ischemia and ReperfusionNitric Oxide and Endothelin EffectsOrgan Transplantation Techniques and Outcomes

The nitric oxide hypothesis of late preconditioning

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Bolli, R., Dawn, B., Tang, X.-L., Qiu, Y., Ping, P., Xuan, Y.-T., Jones, W.K., Takano, H. +2 more·1998·Basic Research in Cardiology
DOI 10.1007/s003950050101PMC PMC3701309
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Abstract

Ischemic preconditioning (PC) occurs in two phases: an early phase, which lasts 2-3 h, and a late phase, which begins 12-24 h later and lasts 3-4 days. The mechanism for the late phase of PC has been the focus of intense investigation. We have recently proposed the "NO hypothesis of late PC", which postulates that NO plays a prominent role both in initiating and in mediating this cardioprotective response. The purpose of this essay is to review the evidence supporting the NO hypothesis of late PC and to discuss its implications. We propose that, on day 1, a brief ischemic stress causes increased production of NO (probably via eNOS) and .O2-, which then react to form ONOO-, ONOO-, in turn, activates the epsilon isoform of protein kinase C (PKC), either directly or via its reactive byproducts such as .OH. Both NO and secondary species derived from .O2- could also stimulate PKC epsilon independently. PKC epsilon activation triggers a complex signaling cascade that involves tyrosine kinases (among which Src and Lck appear to be involved) and probably other kinases, the transcription factor NF-kappa B, and most likely other as yet unknown components, resulting in increased transcription of the iNOS gene and increased iNOS activity on day 2, which is responsible for the protection during the second ischemic challenge. Tyrosine kinases also appear to be involved on day 2, possibly by modulating iNOS activity. According to this paradigm, NO plays two completely different roles in late PC: on day 1, it initiates the development of this response, whereas on day 2, it protects against myocardial ischemia. We propose that two different NOS isoforms are sequentially involved in late PC, with eNOS generating the NO that initiates the development of the PC response on day 1 and iNOS then generating the NO that protects against recurrent ischemia on day 2. The NO hypothesis of late PC puts forth a comprehensive paradigm that can explain both the initiation and the mediation of this complex phenomenon. Besides its pathophysiological implications, this hypothesis has potential clinical reverberations, since NO donors (i.e., nitrates) are widely used clinically and could be used to protect the ischemic myocardium in patients.

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  • NO production plays an important role in the late phase of protection by ischemic preconditioning.

    “and NO production plays an important role in the late phase of protection [117].”

    From Mechanisms of nitrite bioactivation (2014) · cites this paper as [117]

  • Ischemic preconditioning is an effective method of protecting against IR injury.

    “Ischemic preconditioning is an effective method of protecting against IR injury”

    From Mechanisms of nitrite bioactivation (2014) · cites this paper as [117]

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Research works printed but not linked: 12

  1. [2]Banerjee S, Tang X-L, Qiu Y, Takano H, Manchikalapudi S, Dawn B, Shirk G, Bolli R. Nitroglycerin induces late preconditioning against myocardial stunning via protein kinase C mediated pathway in conscious rabbits. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Nitroglycerin%20induces%20late%20preconditioning%20against%20myocardial%20stunning%20via%20protein%20kinase%20C%20mediated%20pathway%20in%20conscious%20rabbits&author=S%20Banerjee&author=X-L%20Tang&author=Y%20Qiu&author=H%20Takano&author=S%20Manchikalapudi&publication_year=1998&)]
  2. [11]Dawn B, Qiu Y, Tang X-L, Takano H, Banerjee S, Bolli R. Involvement of tyrosine kinases in the development of late preconditioning against myocardial stunning in conscious rabbits. J Mol Cell Cardiol. 1998;30:A264. (abstract) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=J%20Mol%20Cell%20Cardiol&title=Involvement%20of%20tyrosine%20kinases%20in%20the%20development%20of%20late%20preconditioning%20against%20myocardial%20stunning%20in%20conscious%20rabbits&author=B%20Dawn&author=Y%20Qiu&author=X-L%20Tang&author=H%20Takano&author=S%20Banerjee&volume=30&publication_year=1998&pages=A264&)]
  3. [12]Dawn B, Qiu Y, Tang X-L, Takano H, Banerjee S, Bolli R. The protective effects of late preconditioning are mediated by tyrosine kinase activity in conscious rabbits. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=The%20protective%20effects%20of%20late%20preconditioning%20are%20mediated%20by%20tyrosine%20kinase%20activity%20in%20conscious%20rabbits&author=B%20Dawn&author=Y%20Qiu&author=X-L%20Tang&author=H%20Takano&author=S%20Banerjee&publication_year=1998&)]
  4. [16]Guo Y, Jones WK, Tang X-L, Wu W-J, Qiu Y, Yang Z, Bao W, Flaherty M, Shirk G, Bolli R. Targeted disruption of iNOS gene abrogates the late phase of ischemic preconditioning. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Targeted%20disruption%20of%20iNOS%20gene%20abrogates%20the%20late%20phase%20of%20ischemic%20preconditioning&author=Y%20Guo&author=WK%20Jones&author=X-L%20Tang&author=W-J%20Wu&author=Y%20Qiu&publication_year=1998&)]
  5. [18]Jones WK, Flaherty MP, Tang X-L, Baner-jee S, Qiu Y, Bolli R. Nitric oxide dependent increase in steady state iNOS transcript levels in a conscious rabbit model of late preconditioning. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Nitric%20oxide%20dependent%20increase%20in%20steady%20state%20iNOS%20transcript%20levels%20in%20a%20conscious%20rabbit%20model%20of%20late%20preconditioning&author=WK%20Jones&author=MP%20Flaherty&author=X-L%20Tang&author=S%20Baner-jee&author=Y%20Qiu&publication_year=1998&)]
  6. [27]Ping P, Zhang J, Cao X, Kong D, Tang X-L, Qiu Y, Manchikalapudi S, Li RCX, Bolli R. Brief episodes of ischemia induce activation of the MEK 1/2 – p44/p42 MAPK signaling cascade in the cytosolic fraction and subsequent nuclear translocation of p44/p42 MAPks via a PKC-depen-dent pathway in conscious rabbits. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Brief%20episodes%20of%20ischemia%20induce%20activation%20of%20the%20MEK%201/2%20%E2%80%93%20p44/p42%20MAPK%20signaling%20cascade%20in%20the%20cytosolic%20fraction%20and%20subsequent%20nuclear%20translocation%20of%20p44/p42%20MAPks%20via%20a%20PKC-depen-dent%20pathway%20in%20conscious%20rabbits&author=P%20Ping&author=J%20Zhang&author=X%20Cao&author=D%20Kong&author=X-L%20Tang&publication_year=1998&)]
  7. [28]Ping P, Li RCX, Zhang J, Kong D, Jones K, Zheng Y-T, Cao X, Bolli R. Identification of two distinct mechanisms for the activation of p44/p42 mitogen activated protein kinases (MAPKs) in vivo by a PKC isoform epsilon dependent signaling pathway in transgenic mice. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Identification%20of%20two%20distinct%20mechanisms%20for%20the%20activation%20of%20p44/p42%20mitogen%20activated%20protein%20kinases%20(MAPKs)%20in%20vivo%20by%20a%20PKC%20isoform%20epsilon%20dependent%20signaling%20pathway%20in%20transgenic%20mice&author=P%20Ping&author=RCX%20Li&author=J%20Zhang&author=D%20Kong&author=K%20Jones&publication_year=1998&)]
  8. [29]Ping P, Zhang J, Li RCX, Tang X-L, Qiu Y, Banerjee S, Zheng Y-T, Bolli R. Ischemic preconditioning (PC) induces selective activation of Src and Lck tyrosine kinases in conscious rabbits via a PKC-dependent pathway. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Ischemic%20preconditioning%20(PC)%20induces%20selective%20activation%20of%20Src%20and%20Lck%20tyrosine%20kinases%20in%20conscious%20rabbits%20via%20a%20PKC-dependent%20pathway&author=P%20Ping&author=J%20Zhang&author=RCX%20Li&author=X-L%20Tang&author=Y%20Qiu&publication_year=1998&)]
  9. [36]Takano H, Tang X-L, Qiu Y, Manchikalapudi S, Wu W-J, French BA, Bolli R. Intracoronary administration of oxygen radicals induces late preconditioning against stunning in conscious rabbits. Circulation. 1997;96(Suppl 1):I-256–I-257. (abstract) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Intracoronary%20administration%20of%20oxygen%20radicals%20induces%20late%20preconditioning%20against%20stunning%20in%20conscious%20rabbits&author=H%20Takano&author=X-L%20Tang&author=Y%20Qiu&author=S%20Manchikalapudi&author=W-J%20Wu&volume=96&issue=Suppl%201&publication_year=1997&pages=I-256-I-257&)]
  10. [38]Takano H, Tang X-L, Qiu Y, Banerjee S, Dawn B, Bolli R. The tetrahydrobiopterin synthesis inhibitor N-acetylserotonin abrogates late preconditioning against myocardial stunning in conscious rabbits. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=The%20tetrahydrobiopterin%20synthesis%20inhibitor%20N-acetylserotonin%20abrogates%20late%20preconditioning%20against%20myocardial%20stunning%20in%20conscious%20rabbits&author=H%20Takano&author=X-L%20Tang&author=Y%20Qiu&author=S%20Banerjee&author=B%20Dawn&publication_year=1998&)]
  11. [42]Tang X-L, Rizvi AN, Qiu Y, Takano H, Zhang Q, Guo Y, Bolli R. Evidence that the hydroxyl radical triggers late preconditioning against myocardial stunning in conscious rabbits. Circulation. 1997;96:I-255. (abstract) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Evidence%20that%20the%20hydroxyl%20radical%20triggers%20late%20preconditioning%20against%20myocardial%20stunning%20in%20conscious%20rabbits&author=X-L%20Tang&author=AN%20Rizvi&author=Y%20Qiu&author=H%20Takano&author=Q%20Zhang&volume=96&publication_year=1997&pages=I-255&)]
  12. [44]Xuan Y-T, Tang X-L, Qiu Y, Banerjee S, Takano H, Han H, Bolli R. Direct evidence that inducible nitric oxide syn-thase mediates the late phase of ischemic preconditioning in conscious rabbits. Circulation. 1998 (abstract, in press) [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Circulation&title=Direct%20evidence%20that%20inducible%20nitric%20oxide%20syn-thase%20mediates%20the%20late%20phase%20of%20ischemic%20preconditioning%20in%20conscious%20rabbits&author=Y-T%20Xuan&author=X-L%20Tang&author=Y%20Qiu&author=S%20Banerjee&author=H%20Takano&publication_year=1998&)]

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Authors
Bolli, R., Dawn, B., Tang, X.-L., Qiu, Y., Ping, P., Xuan, Y.-T., Jones, W. K., Takano, H., Guo, Y., & Zhang, J.
Affiliations
University of Louisville (US)
ORCID
Venue
Basic Research in Cardiology
Publisher
Springer Science and Business Media LLC
Published
1998-10-23
Volume
93
Issue
5
Pages
325-338
ISSN
  • 0003-9217 (ISSN-L)
  • 0300-8428
  • 1435-1803
DOI
10.1007/s003950050101
PMC
PMC3701309
OpenAlex
W1991615080
Cited by
270
References
33
Citations by year
2026: 1 · 2024: 2 · 2023: 2 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 8 · 2016: 5 · 2015: 3 · 2014: 5 · 2013: 7 · 2012: 11
FWCI
14.04
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Basic Research in Cardiology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r29hl058166-03)
  • National Heart, Lung, and Blood Institute (R01 HL 55757, R01-HL-43151, R01HL043151, R37HL055757, R01HL055757, R29 HL-58166)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
  • Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
Keywords
late preconditioning, ischemic preconditioning, nitric oxide, endothelial nitric oxide synthase, inducible nitric oxide synthase, protein kinase C epsilon, superoxide, peroxynitrite, NF-κB, tyrosine kinase, Src kinase, Lck, myocardial ischemia, cardioprotection, nitrate, nitric oxide donors
MeSH terms
Animals, Humans, Myocardium, Nitric Oxide, Myocardial Ischemia, Ischemic Preconditioning, Myocardial

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