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World J Cardiol. Oct 26, 2015; 7(10): 645-651
Published online Oct 26, 2015. doi: 10.4330/wjc.v7.i10.645
Concepts of hypoxic NO signaling in remote ischemic preconditioning
Matthias Totzeck, Ulrike Hendgen-Cotta, Tienush Rassaf
Matthias Totzeck, Ulrike Hendgen-Cotta, Tienush Rassaf, Department of Cardiology, West German Heart and Vascular Center, University of Essen Medical School, 45157 Essen, Germany
Author contributions: Totzeck M, Hendgen-Cotta U and Rassaf T conceived, drafted and approved the manuscript.
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Tienush Rassaf, MD, Professor, Department of Cardiology, West German Heart and Vascular Center, University of Essen Medical School, Hufelandstrasse 55, 45157 Essen, Germany. rassaf@gmx.de
Telephone: +49-201-7234801 Fax: +49-201-7235401
Received: May 29, 2015
Peer-review started: June 1, 2015
First decision: August 4, 2015
Revised: August 17, 2015
Accepted: September 7, 2015
Article in press: September 8, 2015
Published online: October 26, 2015
Processing time: 158 Days and 3.8 Hours
Abstract

Acute coronary syndromes remain a leading single cause of death worldwide. Therapeutic strategies to treat cardiomyocyte threatening ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning (rIPC) applied by brief ischemic episodes to heart-distant organs has been tested in several clinical studies, and the major body of evidence points to beneficial effects of rIPC for patients. The underlying signaling, however, remains incompletely understood. This relates particularly to the mechanism by which the protective signal is transferred from the remote site to the target organ. Many pathways have been forwarded but none can explain the protective effects completely. In light of recent experimental studies, we here outline the current knowledge relating to the generation of the protective signal in the remote organ, the signal transfer to the target organ and the transduction of the transferred signal into cardioprotection. The majority of studies favors a humoral factor that activates cardiomyocyte downstream signaling - receptor-dependent and independently. Cellular targets include deleterious calcium (Ca2+) signaling, reactive oxygen species, mitochondrial function and structure, and cellular apoptosis and necrosis. Following an outline of the existing evidence, we will furthermore characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in rIPC. This refers to the protective role of nitrite, which can be activated endogenously using rIPC and which then contributes to cardioprotection by rIPC.

Keywords: Remote ischemic preconditioning; Ischemia/reperfusion injury; Nitrite; S-nitrosation; Mitochondria

Core tip: Therapeutic strategies to treat ischemia/reperfusion injury are urgently needed. Remote ischemic preconditioning (rIPC) appears to exert beneficial effects for patients. The underlying signaling remains incompletely understood. Following an outline of the existing evidence, we will characterize the existing knowledge and discuss future perspectives with particular emphasis on the interaction between the recently discovered hypoxic nitrite-nitric oxide signaling in rIPC.