Molecular Mechanisms of Angiotensin II–Mediated Mitochondrial Dysfunction: Linking Mitochondrial Oxidative Damage and Vascular Endothelial Dysfunction
Abstract
Mitochondrial dysfunction is a prominent feature of most cardiovascular diseases. Angiotensin (Ang) II is an important stimulus for atherogenesis and hypertension; however, its effects on mitochondrial function remain unknown. We hypothesized that Ang II could induce mitochondrial oxidative damage that in turn might decrease endothelial nitric oxide (NO · ) bioavailability and promote vascular oxidative stress. The effect of Ang II on mitochondrial ROS, mitochondrial respiration, membrane potential, glutathione, and endothelial NO · was studied in isolated mitochondria and intact bovine aortic endothelial cells using electron spin resonance, dihydroethidium high-performance liquid chromatography –based assay, Amplex Red and cationic dye fluorescence. Ang II significantly increased mitochondrial H 2 O 2 production. This increase was blocked by preincubation of intact cells with apocynin (NADPH oxidase inhibitor), uric acid (scavenger of peroxynitrite), chelerythrine (protein kinase C inhibitor), N G -nitro- l -arginine methyl ester (nitric oxide synthase inhibitor), 5-hydroxydecanoate (mitochondrial ATP-sensitive potassium channels inhibitor), or glibenclamide. Depletion of p22 phox subunit of NADPH oxidase with small interfering RNA also inhibited Ang II–mediated mitochondrial ROS production. Ang II depleted mitochondrial glutathione, increased state 4 and decreased state 3 respirations, and diminished mitochondrial respiratory control ratio. These responses were attenuated by apocynin, 5-hydroxydecanoate, and glibenclamide. In addition, 5-hydroxydecanoate prevented the Ang II–induced decrease in endothelial NO · and mitochondrial membrane potential. Therefore, Ang II induces mitochondrial dysfunction via a protein kinase C–dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite. Furthermore, mitochondrial dysfunction in response to Ang II modulates endothelial NO · and generation, which in turn has ramifications for development of endothelial dysfunction.
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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 [242]
Activation of NOX via angiotensin II and the angiotensin II type 1 receptor is mediated by PKC; PKCε is also an activator of the KATP channel, which stimulates mitochondrial ROS production.
“Of note, the activation of NOX via angiotensin II and the angiotensin II type 1 receptor is mediated by PKC; however, the isoform PKCε is also an activator of the KATP channel, which, as indicated, also stimulates mitochondrial ROS production (FIGURE 17) (187, 242).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [242]
Mitochondrial potassium channels are implicated in enhanced mitochondrial ROS generation and increased uncoupling.
“Mitochondrial potassium channels were also implicated in enhanced mitochondrial ROS generation and increased uncoupling.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [121]
Peroxynitrite formation is involved in AII pathways, as uric acid blocks mitochondrial ROS generation and mitochondrial dysfunction, attenuating AII-mediated reduction of ΔΨ and decreased respiratory control ratio.
“peroxynitrite formation was shown to be involved in these pathways as uric acid, a peroxynitrite scavenger, blocked mitochondrial ROS generation and mitochondrial dysfunction, attenuating AII-mediated reduction of ΔΨ, and decreased the respiratory control ratio”
From Redox regulation of mitochondrial function (2012) · cites this paper as [121]
AII-activated NOXs cause mitochondrial dysfunction and upregulate mitochondrial release of oxidants, in part by stimulating ETC-mediated production of ROS.
“AII-activated NOXs were found to cause mitochondrial dysfunction and upregulate mitochondrial release of oxidants, in part, by stimulating ETC-mediated production of ROS (121).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [121]
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- Authors
- Doughan, A. K., Harrison, D. G., & Dikalov, S. I.
- Affiliations
- United States Department of Veterans Affairs (US)
- Venue
- Circulation Research
- Published
- 2008-02-29
- Volume
- 102
- Issue
- 4
- Pages
- 488-496
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W2164444293
- Cited by
- 710
- References
- 43
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 19 · 2023: 32 · 2022: 33 · 2021: 44 · 2020: 39 · 2019: 31 · 2018: 31 · 2017: 36 · 2016: 54 · 2015: 29 · 2014: 58 · 2013: 51 · 2012: 50
- FWCI
- 25.60
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (5p01hl075209-05)
- National Heart, Lung, and Blood Institute (P0-1 HL-075209, R01HL094469, P01HL058000)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Keywords
- angiotensin II, mitochondrial dysfunction, endothelial nitric oxide, NADPH oxidase, peroxynitrite, protein kinase C, mitochondrial reactive oxygen species, mitochondrial glutathione, mitochondrial respiration, endothelial dysfunction, oxidative stress, atherogenesis, hypertension
- MeSH terms
- Angiotensin II, Animals, Aorta, Cattle, Cells, Cultured, Glutathione, Hydrogen Peroxide, Mitochondria, Nitric Oxide, Superoxides, Vascular Diseases, Vasoconstrictor Agents, Oxidative Stress, Cell Respiration, Mitochondrial Diseases, Endothelial Cells, Membrane Potential, Mitochondrial
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