title: Concepts of hypoxic NO signaling in remote ischemic preconditioning.
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 (Ca(2+)) 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.
authors.affiliation: Matthias Totzeck, Ulrike Hendgen-Cotta, Tienush Rassaf, Department of Cardiology, West German Heart and Vascular Center, University of Essen Medical School, 45157 Essen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Totzeck
authors.affiliation: Matthias Totzeck, Ulrike Hendgen-Cotta, Tienush Rassaf, Department of Cardiology, West German Heart and Vascular Center, University of Essen Medical School, 45157 Essen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hendgen-Cotta
authors.affiliation: Matthias Totzeck, Ulrike Hendgen-Cotta, Tienush Rassaf, Department of Cardiology, West German Heart and Vascular Center, University of Essen Medical School, 45157 Essen, Germany.
authors.forename: Tienush
authors.initials: T
authors.lastname: Rassaf
keywords: Ischemia/reperfusion injury; Mitochondria; Nitrite; Remote ischemic preconditioning; S-nitrosation