Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2019 Oct 11;20(20):5034.
doi: 10.3390/ijms20205034.

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

Free PMC article

Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies

Ricardo O S Soares et al. Int J Mol Sci. .
Free PMC article


Ischemia/reperfusion injury (IRI) permeates a variety of diseases and is a ubiquitous concern in every transplantation proceeding, from whole organs to modest grafts. Given its significance, efforts to evade the damaging effects of both ischemia and reperfusion are abundant in the literature and they consist of several strategies, such as applying pre-ischemic conditioning protocols, improving protection from preservation solutions, thus providing extended cold ischemia time and so on. In this review, we describe many of the latest pharmacological approaches that have been proven effective against IRI, while also revisiting well-established concepts and presenting recent pathophysiological findings in this ever-expanding field. A plethora of promising protocols has emerged in the last few years. They have been showing exciting results regarding protection against IRI by employing drugs that engage several strategies, such as modulating cell-surviving pathways, evading oxidative damage, physically protecting cell membrane integrity, and enhancing cell energetics.

Keywords: RISK pathway; SAFE pathway; cyclic guanosine 3′,5′-monophosphate/Protein Kinase G pathway; inflammation; ischemia/reperfusion injury; mitochondria; pro-survival pathways; reactive oxygen species.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
Figure 1
Proposed mechanism of impaired endothelium-dependent vasodilation after coronary reperfusion injury. Upon reperfusion, free radicals from a variety of sources induce injury to G-proteins (Gp) that link intracellular processes. Two possible sites of injury in the present model are the signal transduction pathway between the cell receptor (R) and phospholipase C (PLC) and the pathway that activates the influx of extracellular calcium for sustained production of endothelium-derived nitric oxide (NO). (DAG = diacylglycerol, IP3 = inositol trisphosphate, PIP2 = phosphatidylinositol 4,5-biphosphate, (−) = inhibits, (+) = stimulates.) (Adapted from Evora et al. [4]).
Figure 2
Figure 2
Simplified overview of the signaling pathways in the target cells presented in this review that are relevant for the development of a pharmacological therapy rationale. Systemic modulators were excluded from the figure. The RISK pathway (in green) is commonly activated via G-protein coupled receptors by opioids, bradykinin, and adenosine or the receptor tyrosine kinase, by erythropoietin, cytokines, insulin or insulin-like growth factor-1. The cGMP/PKG pathway (in green) receives external stimuli through the activation of the natriuretic peptide receptor, by natriuretic peptides A and B (ANP, BNP). The SAFE pathway is engaged via the glycoprotein 130 receptor or TNF-α receptor type 2 by IL-6, IL-11, leukemia inhibitory factor (LIF) or TNF-a. A fourth pathway, the TNF- α receptor type-1 is the only of deleterious character depicted in this figure. The xanthine-oxidase (XO) and sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pathways are shown only in order to highlight their targets. Pointed arrows mean stimulation, blunt arrows mean inhibition.

Similar articles

See all similar articles

Cited by 1 article


    1. Carden D.L., Granger D.N. Pathophysiology of ischaemia-reperfusion injury. J. Pathol. 2000;190:255–266. doi: 10.1002/(SICI)1096-9896(200002)190:3<255::AID-PATH526>3.0.CO;2-6. - DOI - PubMed
    1. Evora P.R., Pearson P.J., Schaff H.V. Endothelial function and coronary vasospasm after heart surgery. Arq. Bras. Cardiol. 1993;61:119–125. - PubMed
    1. Evora P.R., Pearson P.J., Seccombe J.F., Schaff H.V. Ischemia-reperfusion lesion. Physiopathologic aspects and the importance of the endothelial function. Arq. Bras. Cardiol. 1996;66:239–245. - PubMed
    1. Evora P.R., Pearson P.J., Schaff H.V. Impaired endothelium-dependent relaxation after coronary reperfusion injury: Evidence for G-protein dysfunction. Ann. Thorac. Surg. 1994;57:1550–1556. doi: 10.1016/0003-4975(94)90121-X. - DOI - PubMed
    1. Ibanez B., Heusch G., Ovize M., Van De Werf F. Evolving Therapies for Myocardial Ischemia/Reperfusion Injury. J. Am. Coll. Cardiol. 2015;65:1454–1471. doi: 10.1016/j.jacc.2015.02.032. - DOI - PubMed

MeSH terms