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Cited by 273Cardiac Ischemia and ReperfusionCardiac electrophysiology and arrhythmiasRedox biology and oxidative stress

The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.

Study of the mechanisms of hydrogen peroxide and hydroxyl free radical-induced cellular injury and calcium overload in cardiac myocytes

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Josephson, R A, Silverman, H S, Lakatta, E G, Stern, M D, Zweier, J L·1991·Journal of Biological Chemistry
DOI 10.1016/s0021-9258(18)52251-1
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Abstract

There is evidence that myocardial injury, as would occur on post-ischemic reperfusion, may be caused by the generation of oxygen radicals, as well as by the induction of intracellular calcium overload; however, the relationship between these two mechanisms of injury is not known. To test the hypothesis that oxidants and oxygen radicals can cause cardiac myocyte injury and intracellular calcium overload, isolated adult rat ventricular myocytes were exposed to H2O2 (1-10 mM) and Fe3(+)-nitrilotriacetate. EPR measurements confirmed the production of the highly reactive .OH radical by this system. The oxygen radical generating system initially caused a transient augmentation of twitch amplitude in single field stimulated myocytes. This was followed by contractile oscillations occurring during the twitch prior to full cell relaxation, and spontaneous mechanical oscillations occurring between electrically stimulated contractions. Eventually, cells became inexcitable and abruptly underwent contracture. In the presence of lower bathing calcium concentrations, these oxidant-induced alterations were prevented or delayed. However, cells exposed to the radical generating system in the absence of extracellular calcium still eventually underwent contracture but stimulated contractions or mechanical oscillations were not seen. Measurements in single myocytes loaded with the fluorescent probe of intracellular calcium, Indo-1, demonstrated a rise in both systolic and diastolic fluorescence ratio, as well as oscillations and widening of the fluorescence transient, suggestive of cellular calcium loading, following exposure to the radical generating system. Injured myocytes did not take up trypan blue dye. Contractile dysfunction and calcium channel blocker, nitrendipine. NMR measurements of cellular [ATP] demonstrated that these alterations in cellular calcium preceded the depletion of ATP. Subsequent depletion of ATP was accompanied by the appearance of increased concentrations of sugar phosphates indicative of a block in glycolysis and ATP depletion correlated with cellular rigor. Thus, oxygen free radicals can cause cardiac myocyte injury with contractile abnormalities which occur due to myocyte calcium loading. The mechanism of oxidant-induced calcium loading is not due to nonspecific membrane damage, or energy depletion, but rather due to increased calcium influx through voltage gated calcium channels. This early calcium overload state as well as oxidant induced block of glycolysis result in cellular energy depletion and cell death with the induction of contracture.

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Research works printed but not linked: 6

  1. Murphy, 1987, Circulation, 75, V-15
  2. Weiss, 1990, J. Clin. Invest.
  3. Spurgeon, 1990, Am. J. Physiol., 258, H574
  4. Silver, 1983, Am. J. Physiol., 245, H891
  5. Stuart, 1989, Biophys. J., 55, 15a
  6. Bremel, 1972, Nature, 238, 97

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Metadata

Authors
Josephson, R. A., Silverman, H. S., Lakatta, E. G., Stern, M. D., & Zweier, J. L.
Affiliations
Johns Hopkins University (US)
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
1991-02
Volume
266
Issue
4
Pages
2354-2361
ISSN
0021-9258 (ISSN-L)
DOI
10.1016/s0021-9258(18)52251-1
OpenAlex
W1556814137
Cited by
272
References
31
Citations by year
2024: 2 · 2023: 5 · 2021: 2 · 2020: 1 · 2019: 4 · 2018: 5 · 2017: 7 · 2016: 2 · 2015: 8 · 2014: 4 · 2013: 8 · 2012: 11
FWCI
12.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (5p50hl017655-17)
  • National Heart, Lung, and Blood Institute (HL-38324, HL-07227, HL-17655-13)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Ischemia and Reperfusion
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Keywords
hydrogen peroxide, hydroxyl radicals, oxygen free radicals, calcium overload, cardiomyocytes, myocardial injury, contractile dysfunction, calcium influx, voltage-gated calcium channels, ATP depletion, cell death, nitrendipine
MeSH terms
Adenosine Triphosphate, Animals, Calcium, Electric Stimulation, Electron Spin Resonance Spectroscopy, Ferric Compounds, Free Radicals, Hydrogen Peroxide, Hydrogen-Ion Concentration, Hydroxides, Kinetics, Male, Myocardial Contraction, Myocardium, Nitrilotriacetic Acid, Magnetic Resonance Spectroscopy, Rats, Inbred Strains, Hydroxyl Radical, Rats

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