Nitrite activates protein kinase A in normoxia to mediate mitochondrial fusion and tolerance to ischaemia/reperfusion

Abstract

These data are the first to demonstrate nitrite-dependent normoxic modulation of both mitochondrial morphology and function and reveal a novel signalling pathway responsible for nitrite-mediated cardioprotection.

Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning

“…This unexpected result may be due to the pleiotropic nonfusion effects of these mitochondrial fusion proteins that include apoptosis induction, mediation of mitophagy, and tethering the sarcoplasmic reticulum to the mitochondria (de Brito and Scorrano, 2008a,b;Wang et al, 2012). A recent study has shown that pharmacologic preconditioning using nitrite protected a cardiac cell line by inhibiting ischemia-induced mitochondrial fission through the activation of protein kinase A (Pride et al, 2014). Whether ischemic preconditioning and postconditioning exert their cardioprotective effect by modulating mitochondrial morphology is not known.…”

Nitrite Confers Preconditioning and Cytoprotection After Ischemia/Reperfusion Injury Through the Modulation of Mitochondrial Function

“…It is also recognized that several modalities of pharmacological preconditioning and ischemic preconditioning involve the modulation of mitochondrial number and function (23,97,139,149). Consistent with this, accumulating data demonstrates that nitrite regulates mitochondrial number, function and morphology in both ischemic and non-hypoxic conditions (37,50,86,103,109,120,121,145,191). This review will provide an overview of the preclinical studies demonstrating nitrite-mediated protection, focus on the distinct mechanisms by which nitrite regulates hypoxic and non-hypoxic mitochondrial function and discuss the contribution of these mechanisms to nitrite-mediated preconditioning and cytoprotection after I/R.…”

“…We have shown in vivo that administration of one dose of nitrite by oral gavage 24 hours prior to the ischemic episode confers protection in a murine model of myocardial infarction or hepatic I/R (195). Further, hearts isolated from rats given one dose of intraperitoneal nitrite show a significant decrease in infarct size and protection of left ventricular developed pressure after ex vivo global ischemia/reperfusion (103). It is important to note that the half-life of nitrite in blood and in the non-hypoxic heart and liver is less than one hour (43,47) suggesting that the nitrite administered systemically to non-hypoxic animals in these studies is fully metabolized well before the tissue is exposed to ischemia.…”

“…Beyond hypoxic reduction of nitrite, several recent studies have also shown that NO 2 -mediates beneficial effects, such as regulation of glucose uptake (109), propagation of myoblast proliferation (215), stimulation of wound repair (225) and preconditioning (103), that do not appear to be dependent on its reduction to NO. While the exact chemical pathway by which NO 2 -mediates these effects is still under investigation, a number of chemical mechanisms could be operative including protein nitration, nitrated lipid formation or other heme peroxidase catalyzed oxidative pathways (Figure 1).…”

“…However, a number of studies have now demonstrated that nitrite is a pharmacological preconditioning agent, which mediates cytoprotection when administered for a brief period 1-24 hours prior to the ischemic episode (21,61,181,195), and this effect may be independent of its hypoxic reduction to NO (103). It has now also emerged that nitrite plays a critical role as a physiological signaling molecule in the phenomenon of remote ischemic conditioning (183), whereby the application of several brief cycles of I/R to one organ or area protects a distant organ from a subsequent prolonged ischemic episode.…”