J Thorac Cardiovasc Surg 2006;131:507-509
© 2006 The American Association for Thoracic Surgery
Linking gene expression, nuclear factor kappa B, remote ischemic preconditioning, and transplantation: A quest for an elusive Holy Grail or a road to an amazing discovery?
Igor E. Konstantinov, MD, PhD,
Andrew N. Redington, MD
Divisions of Cardiovascular Surgery and Cardiology, Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, M5G 1X8, Ontario, Canada
To the Editor:
We read with interest the recent paper of Ishiyama and colleagues
reporting that inhibition of nuclear factor kappa B (NF-B) by IB supressor gene transfer ameliorated ischemia-reperfusion (IR) injury after experimental lung transplantation. A few comments seem appropriate.
Is activation of NF-B before transplantation destructive or protective? Two murine studies provided seemingly contradictory results. In the study of Ishiyama and colleagues,
inhibition of NF-B rendered protection against the IR injury, yet in another study
a targeted deletion of the p105 subunit of the NF-B abolished the protective effect of the remote ischemic preconditioning (rIPC), a novel clinically applicable mode of protection against IR injury, whereby the organs can be protected by a brief ischemia applied remotely (eg, limb ischemia). Gene expression appears to play an important role in rIPC. In our own studies, the rIPC stimulus modified NF-B regulated gene expression in leukocytes
and the target organ,
and when the rIPC was applied to the recipient in porcine model it rendered myocardial protection after the orthotopic heart transplantation.
It is widely known that the transcription factor NF-B can be activated by a variety of stimuli, for example, tumor necrosis factor (TNF)-, bacterial lipopolysaccharide (LPS), and heat shock protein (HSP). Stimulation of the cell may lead to phosphorylation of IB and translocation of NF-B into the nucleus, resulting in gene expression, including those genes responsible for exocytosis of adhesive molecules and cytokine production in leukocytes, but also for production of protective substances eg, manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS)
(Figure 1). It is perhaps less known, however, that the "classic" NF-B exists as a p50-p65 heteromer. The p50 derives from the precursor protein p105, which appears to be indispensable for rIPC.
Suppression of gene expression of NF-B p65 subunit by the rIPC stimulus observed in our study
was of special interest because this might be a potential site of uncoupling of production of cytokines and MnSOD/iNOS synthesis (Figure 1). It appears that the initial TNF- signaling pathway activation by rIPC induces protective MnSOD synthesis, but yet suppresses gene expression responsible for subsequent cytokine production and TNF- signaling pathway restoration. Taking into consideration that general nonspecific inhibition of transcription by actinomycin-D abolishes protection of ischemic preconditioning, it seems likely that a brief activation of NF-B might be protective, while its sustained activation may have detrimental results. Or, perhaps, a unit-specific activation of the NF-B is more important?
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Figure 1. Innate immunity pathways and NF B. Remote ischemic preconditioning stimulus upregulates (red) and downregulates (green) gene expression of intracellular inflammatory pathways. HSP, Heat shock protein; LPS, lipopolysaccharide; LBP, LPS binding protein; TLR, toll-like receptor; IRAK, interleukin (IL)-1 receptor associated kinase; TIR, toll/IL-1/plan R homology domain; IKK, I-B kinase; MnSOD, manganese superoxide dismutase. (From Konstantinov IE, Arab S, Kharbanda RK, Li J, Cheung MM, Cherepanov V, et al. The Remote Ischemic Preconditioning Stimulus Modifies Inflammatory Gene Expression in Humans. Physiol Genomics. 2004;19:143-50; used with permission of The American Physiological Society.)|
Further research of NF-B involvement in IR injury, particularly in transplantation, could be an area where the major discoveries in cardiothoracic surgery may be made.
- Ishiyama T, Dharmarajan S, Hayama M, Moriya H, Grapperhaus K, Patterson GA. Inhibition of nuclear factor B by IB superrepressor gene transfer ameliorates ischemia-reperfusion injury after experimental lung transplantation. J Thorac Cardiovasc Surg 2005;130:194-201.[Abstract/Free Full Text]
- Li G, Labruto F, Sirsjo A, Chen F, Vaage J, Valen G. Myocardial protection by remote preconditioning. the role of nuclear factor kappa-B p105 and inducible nitric oxide synthase. Eur J Cardiothorac Surg 2004;26:968-973.[Abstract/Free Full Text]
- Konstantinov IE, Arab S, Kharbanda RK, et al. The remote ischemic preconditioning stimulus modifies inflammatory gene expression in humans. Physiol Genomics 2004;19:143-150.[Abstract/Free Full Text]
- Konstantinov IE, Arab S, Li J, Coles JG, Boscarino C, Mori A, et al. The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg 2005;130:1326-1332.[Abstract/Free Full Text]
- Konstantinov IE, Li J, Cheung MM, Shimizu M, Stokoe J, Kharbanda RK, et al. Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism. Transplantation 2005;79:1691-1695.[Medline]