Role of NAD(P)H Oxidase- and Mitochondria-Derived Reactive Oxygen Species in Cardioprotection of Ischemic Reperfusion Injury by Angiotensin II
Abstract
Reactive oxygen species (ROS) participate in cardioprotection of ischemic reperfusion (I/R) injury via preconditioning mechanisms. Mitochondrial ROS have been shown to play a key role in this process. Angiotensin II (Ang II) exhibits pharmacological preconditioning; however, the involvement of NAD(P)H oxidase, known as an ROS-generating enzyme responsive to Ang II stimuli, in the preconditioning process remains unclear. We compared the effects of 5-hydroxydecanoate (5-HD; an inhibitor of mitochondrial ATP-sensitive potassium channels), apocynin (an NAD(P)H oxidase inhibitor), and 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (tempol; a membrane permeable radical scavenger) on pharmacological preconditioning by Ang II in rat cardiac I/R injury in vivo. Treatment with a pressor dose of Ang II before a 30-minute coronary occlusion reduced infarct size as determined 24 hours after reperfusion. The protective effects of Ang II were eliminated by pretreatment with 5-HD or apocynin, similar to tempol. Both 5-HD and apocynin suppressed the enhanced cardiac lipid peroxidation and activation of the apoptosis signal-regulating kinase/p38, c-Jun NH 2 -terminal kinase (JNK) pathways, but not the Raf/MEK/extracellular signal-regulated kinase pathway, elicited by acutely administered Ang II. Apocynin but not 5-HD suppressed Ang II–induced augmentations of the NAD(P)H oxidase complex formation (p47 phox , p22 phox , and Rac-1) and its activity in the heart. Finally, 5-HD suppressed superoxide production by isolated cardiac mitochondria without any effect on their respiration. These results suggest that the preconditioning effects of Ang II for cardiac I/R injury may be mediated by cardiac mitochondria-derived ROS enhanced through NAD(P)H oxidase via JNK and p38 mitogen-activated protein kinase activation.
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The increase of mitochondrial ROS production after angiotensin II-induced activation of NOX appears to require the function of mitochondrial ATP-dependent potassium channels (KATP).
“This process appears to require the function of mitochondrial ATP-dependent potassium channels (KATP), as shown by the ability of KATP inhibitors to block the increase of mitochondrial ROS production after angiotensin II–induced activation of NOX (242, 507).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [507]
ROS are produced not only during reperfusion and reoxygenation after ischemia or hypoxia, but also during ischemia and hypoxia.
“During the last decade, it has become increasingly clear that ROS are produced not only during reperfusion and reoxygenation after ischemia or hypoxia, but also during ischemia (Figs. 17–19) (5, 28, 70, 181–183, 247, 269, 270, 298, 317) and hypoxia (316).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [183]
The mitochondrion likely releases small amounts of H2O2 as a natural chemical messenger in the modulation of mitochondrial and cellular function.
“Although the mitochondrion is largely a sink for O2•− and H2O2 due to its ROS scavenger systems, it likely releases small amounts of H2O2 as a natural chemical messenger in the modulation of mitochondrial and cellular function (27, 113, 126, 183, 203, 206).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [183]
Mitochondrial KCa openers, like KATP channel openers, appear to mediate their effects through ROS-dependent mechanisms, as ROS scavengers such as MnTBAP block the protection.
“Mitochondrial KCa openers, like KATP channel openers, appear to mediate their effects through ROS-dependent mechanisms, as ROS scavengers, such as MnTBAP, block the protection (Figs. 18 and 19) (181, 183, 298).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [183]
ROS trigger or mediate ischemic and pharmacologic preconditioning of hearts.
“It is now well known that ROS trigger or mediate ischemic and pharmacologic preconditioning of hearts (15, 27, 102, 181, 183, 248, 254, 303).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [183]
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- Authors
- Kimura, S., Zhang, G.-X., Nishiyama, A., Shokoji, T., Yao, L., Fan, Y.-Y., Rahman, M., Suzuki, T., Maeta, H., & Abe, Y.
- Affiliations
- Kagawa University (JP)
- Venue
- Hypertension
- Published
- 2005-05
- Volume
- 45
- Issue
- 5
- Pages
- 860-866
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2031258385
- Cited by
- 264
- References
- 36
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 5 · 2021: 7 · 2020: 7 · 2019: 13 · 2018: 5 · 2017: 10 · 2016: 11 · 2015: 6 · 2014: 19 · 2013: 19 · 2012: 26
- FWCI
- 12.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- NADPH oxidase, mitochondrial reactive oxygen species, ischemia-reperfusion injury, cardioprotection, angiotensin II, pharmacological preconditioning, 5-hydroxydecanoate, apocynin, tempol, JNK, p38 MAPK, lipid peroxidation, apoptosis, superoxide, Rac1, p47phox, p22phox, infarct size
- MeSH terms
- Acetophenones, Angiotensin II, Animals, Cardiotonic Agents, Decanoic Acids, Enzyme Activation, Enzyme Inhibitors, Hydroxy Acids, Mitochondria, Myocardium, Phagocytes, Superoxides, Lipid Peroxidation, Myocardial Reperfusion Injury, Reactive Oxygen Species, Ischemic Preconditioning, Myocardial, NADPH Oxidases, Mitogen-Activated Protein Kinases, Rats
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