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Cited by 97Cardiac Ischemia and ReperfusionMitochondrial Function and PathologyCell death mechanisms and regulation

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

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Pride, Christelle Kamga, Mo, Li, Quesnelle, Kelly, Dagda, Ruben K., Murillo, Daniel, Geary, Lisa, Corey, Catherine, Portella, Rafael +6 more·2014·Cardiovascular Research
DOI 10.1093/cvr/cvt224PMC PMC3868348
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Abstract

AIMS: Nitrite (NO2(-)), a dietary constituent and nitric oxide (NO) oxidation product, mediates cardioprotection after ischaemia/reperfusion (I/R) in a number of animal models when administered during ischaemia or as a pre-conditioning agent hours to days prior to the ischaemic episode. When present during ischaemia, the reduction of nitrite to bioactive NO by deoxygenated haem proteins accounts for its protective effects. However, the mechanism of nitrite-induced pre-conditioning, a normoxic response which does not appear to require reduction of nitrite to NO, remains unexplored. METHODS AND RESULTS: Using a model of hypoxia/reoxygenation (H/R) in cultured rat H9c2 cardiomyocytes, we demonstrate that a transient (30 min) normoxic nitrite treatment significantly attenuates cell death after a hypoxic episode initiated 1 h later. Mechanistically, this protection depends on the activation of protein kinase A, which phosphorylates and inhibits dynamin-related protein 1, the predominant regulator of mitochondrial fission. This results morphologically, in the promotion of mitochondrial fusion and functionally in the augmentation of mitochondrial membrane potential and superoxide production. We identify AMP kinase (AMPK) as a downstream target of the mitochondrial reactive oxygen species (ROS) generated and show that its oxidation and subsequent phosphorylation are essential for cytoprotection, as scavenging of ROS prevents AMPK activation and inhibits nitrite-mediated protection after H/R. The protein kinase A-dependent protection mediated by nitrite is reproduced in an intact isolated rat heart model of I/R. CONCLUSIONS: 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.

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Crossref · 10.1093/cvr/cvt224

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  • Mitochondrial hydrogen peroxide can oxidize the catalytic subunit of AMP kinase, leading to its autophosphorylation and activation to modulate metabolism.

    “Mitochondrial hydrogen peroxide can oxidize the catalytic subunit of AMP kinase, leading to its autophosphorylation and subsequent activation to modulate metabolism within the cell (481, 1067).”

    From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [481]

  • In cultured rat H9c2 cardiomyoblasts treated with H/R, preconditioning with nitrite markedly attenuated cell death following hypoxia.

    “In cultured rat H9c2 cardiomyoblasts treated with H/R, preconditioning with nitrite markedly attenuated cell death following hypoxia [135].”

    From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [135]

  • Nitrite protected the heart against I/R injury through the activation of protein kinase A.

    “Notably, in vivo animal study showed consistent results that nitrite protected the heart against I/R injury through the activation of protein kinase A [135].”

    From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [135]

  • Activation of AMPK signaling is required for the cardioprotective effect of nitrite in the preconditioning stage of I/R.

    “The activation of AMPK signaling is required for the cardioprotective effect of nitrite in the preconditioning stage of I/R [135].”

    From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [135]

  • Nitrite activated protein kinase A, which in turn suppressed DRP1-dependent mitochondrial fission, augmented ΔΨm, and promoted superoxide production.

    “Further mechanism studies showed that nitrite activated protein kinase A, which in turn suppressed DRP1-dependent mitochondrial fission, augmented ΔΨm, and promoted superoxide production [135].”

    From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [135]

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Authors
Pride, C. K., Mo, L., Quesnelle, K., Dagda, R. K., Murillo, D., Geary, L., Corey, C., Portella, R., Zharikov, S., St Croix, C., Maniar, S., Chu, C. T., K. H. Khoo, N., & Shiva, S.
Affiliations
University of Pittsburgh (US)
Corresponding author
Shiva, Sruti
ORCID
Venue
Cardiovascular Research
Publisher
Oxford University Press (OUP)
Published
2013-09-30
Volume
101
Issue
1
Pages
57-68
ISSN
  • 0008-6363 (ISSN-L)
  • 1755-3245
DOI
10.1093/cvr/cvt224
PMC
PMC3868348
OpenAlex
W2105374605
Cited by
97
References
24
Citations by year
2026: 4 · 2025: 2 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 17 · 2016: 11 · 2015: 15 · 2014: 10
FWCI
8.99
Type
journal article
Language
en
Open access
Locations
  • Cardiovascular Research (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL096973)
  • National Institute of Neurological Disorders and Stroke (R01NS065789)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords
nitrite, protein kinase A, mitochondrial fusion, ischemia-reperfusion injury, cardioprotection, hypoxia/reoxygenation, Drp1, mitochondrial fission, AMP kinase, reactive oxygen species, mitochondrial membrane potential, superoxide, cardiomyocytes, preconditioning
MeSH terms
Animals, Hypoxia, Cell Line, Male, Nitrites, Phosphorylation, Superoxides, Rats, Sprague-Dawley, Cyclic AMP-Dependent Protein Kinases, Ischemic Preconditioning, Myocardial, Cytoprotection, Dynamins, Rats, AMP-Activated Protein Kinases, Mitochondrial Dynamics

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