Abstract
Donors of nitroxyl (HNO), the one electron-reduction product of nitric oxide (NO.), positively modulate cardiac contractility/relaxation while limiting ischemia-reperfusion (I/R) injury. The mechanisms underpinning HNO anti-ischemic effects remain poorly understood. Using isolated perfused rat hearts subjected to 30 min global ischemia/1 or 2 h reperfusion, here we tested whether, in analogy to NO., HNO protection requires PKCε translocation to mitochondria and KATP channels activation. To this end, we compared the benefits afforded by ischemic preconditioning (IPC; 3 cycles of I/R) with those eventually granted by the NO. donor, diethylamine/NO, DEA/NO, and two chemically unrelated HNO donors: Angeli’s salt (AS, a prototypic donor) and isopropylamine/NO (IPA/NO, a new HNO releaser). All donors were given for 19 min before I/R injury. In control I/R hearts (1 h reperfusion), infarct size (IS) measured via tetrazolium salt staining was 66 ± 5.5% of the area at risk. Both AS and IPA/NO were as effective as IPC in reducing IS [30.7 ± 2.2 (AS), 31 ± 2.9 (IPA/NO), and 31 ± 0.8 (IPC), respectively)], whereas DEA/NO was significantly less so (36.2 ± 2.6%, p < 0.001 vs. AS, IPA/NO, or IPC). IPA/NO protection was still present after 120 min of reperfusion, and the co-infusion with the PKCε inhibitor (PKCV1-2500 nM) prevented it (IS = 30 ± 0.5 vs. 61 ± 1.8% with IPA/NO alone, p < 0.01). Irrespective of the donor, HNO anti-ischemic effects were insensitive to the KATP channel inhibitor, 5-OH decanoate (5HD, 100 μM), that, in contrast, abrogated DEA/NO protection. Finally, both HNO donors markedly enhanced the mitochondrial permeability transition pore (mPTP) ROS threshold over control levels (≅35–40%), an action again insensitive to 5HD. Our study shows that HNO donors inhibit mPTP opening, thus limiting myocyte loss at reperfusion, a beneficial effect that requires PKCε translocation to the mitochondria but not mitochondrial K+ channels activation.
Highlights
To validate that HNO donors can protect the myocardium against interruption and reperfusion for min (I/R) injury, we infused an equivalent dose of IPA/NO as a pretreatment to avoid possible confounding effects from nitrite release
HNO/nitrite releasers, such as AS; HNO protection is mediated by PKCε-dependent signaling, but is independent from mito-KATP channel activation; Mitochondrial protection triggered by HNO donors is the result of desensitizing the mitochondrial permeability transition pore (mPTP) to reactive oxygen species (ROS), which, in turn, delays opening of the pore, reducing cell damage as a result of ischemia-reperfusion injury
We have previously demonstrated that mPTP is the endeffector of protection signaling in the heart and inhibition of mPTP opening with certain pharmacological agents, including the mito-KATP channel openers, which protect the heart, and that the enhancement of transition pore (mPTP) ROS threshold (tmPTP) is directly linked to the level of cell protection [19]
Summary
It is well consolidated that the vast majority of myocardial cell death that concoct the final infarct intervenes during ischemia and the very first few minutes of reperfusion [1]. Antioxidants 2022, 11, 382 infarction (MI) would result in better clinical outcomes, i.e., more effective prevention of post-ischemic heart failure (HF). In cardiac I/R injury, the protective role of gasotransmitters such as nitric oxide A low concentration of this gasotransmitter can increase cardiomyocyte function [4]. Concentrations can achieve quite the opposite effects, i.e., impaired cardiomyocyte function and mitochondrial respiration, as well as enhanced inflammation. All of these events can lead to worsened post-MI outcomes, owing to exacerbated cell death.
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