Alterations in zinc homeostasis underlie endothelial cell death induced by oxidative stress from acute exposure to hydrogen peroxide

Dean A. Wiseman, Sandra M. Wells, Maryann Hubbard, Jonathan E. Welker, Stephen M. Black

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Oxidative stress has been associated with multiple pathologies and disease states, including those involving the cardiovascular system. Previously, we showed that pulmonary artery endothelial cells (PAECs) undergo apoptosis after acute exposure to H2O2. However, the underlying mechanisms regulating this process remain unclear. Because of the prevalence of H 2O2 in normal physiological processes and apparent loss of regulation in disease states, the purpose of this study was to develop a more complete understanding of H2O2-mediated adverse effects on endothelial cell survival. Acute exposure of PAECs to H2O 2 caused a dose-dependent increase in cellular release of lactate dehydrogenase and a significant increase in production of superoxide ions, which appear to be generated within the mitochondria, as well as a significant loss of mitochondrial membrane potential and activity. Subsequent to the loss of mitochondrial membrane potential, PAECs exhibited significant caspase activation and apoptotic nuclei. We also observed a significant increase in intracellular free Zn2+ after bolus exposure to H2O2. To determine whether this increase in Zn2+ was involved in the apoptotic pathway induced by acute H2O2 exposure, we developed an adenoviral construct for overexpression of the Zn2+-binding protein metallothionein-1. Our data indicate that chelating Zn2+, either pharmacologically with N,N,N′,N-tetrakis(2-pyridylmethyl)ethylene diamine or by overexpression of the Zn2+-binding protein metallothionein-1, in PAECs conferred significant protection from induction of apoptosis and cell death associated with the effects of acute H2O2 exposure. Our results show that the acute toxicity profile of H2O2 can be attributed, at least in part, to liberation of Zn2+ within PAECs. We speculate that regulation of Zn2+ levels may represent a potential therapeutic target for cardiovascular disease associated with acute oxidative stress.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume292
Issue number1
DOIs
StatePublished - Jan 1 2007

Fingerprint

Hydrogen Peroxide
Zinc
Oxidative Stress
Homeostasis
Cell Death
Endothelial Cells
Pulmonary Artery
Metallothionein
Mitochondrial Membrane Potential
Carrier Proteins
Apoptosis
Physiological Phenomena
Diamines
Caspases
Cardiovascular System
L-Lactate Dehydrogenase
Superoxides
Cell Survival
Mitochondria
Cardiovascular Diseases

Keywords

  • Apoptosis
  • Cell signaling/signal transduction
  • Metallothionein-1
  • Oxidant stress

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Alterations in zinc homeostasis underlie endothelial cell death induced by oxidative stress from acute exposure to hydrogen peroxide. / Wiseman, Dean A.; Wells, Sandra M.; Hubbard, Maryann; Welker, Jonathan E.; Black, Stephen M.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 292, No. 1, 01.01.2007.

Research output: Contribution to journalArticle

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