Faculty Collaboration Database

Effect of nitric oxide on naphthoquinone toxicity in endothelial cells: role of bioenergetic dysfunction and poly (ADP-ribose) polymerase activation. Biochemistry 2013 Jun 25;52(25):4364-72

Date

05/31/2013

Pubmed ID

23718265

Pubmed Central ID

PMC4028014

DOI

10.1021/bi400342t

Scopus ID

2-s2.0-84879545058 (requires institutional sign-in at Scopus site)   21 Citations

Abstract

When produced at physiological levels, reactive oxygen species (ROS) can act as signaling molecules to regulate normal vascular function. Produced under pathological conditions, ROS can contribute to the oxidative damage of cellular components (e.g., DNA and proteins) and trigger cell death. Moreover, the reaction of superoxide with nitric oxide (NO) produces the strong oxidant peroxynitrite and decreases NO bioavailability, both of which may contribute to activation of cell death pathways. The effects of ROS generated from the 1,4-naphthoquinones alone and in combination with NO on the activation status of poly(ADP-ribose) polymerase (PARP) and cell viability were examined. Treatment with redox cycling quinones activates PARP, and this stimulatory effect is attenuated in the presence of NO. Mitochondria play a central role in cell death signaling pathways and are a target of oxidants. We show that simultaneous exposure of endothelial cells to NO and ROS results in mitochondrial dysfunction, ATP and NAD(+) depletion, and cell death. Alone, NO and ROS have only minor effects on cellular bioenergetics. Further, PARP inhibition does not attenuate reduced cell viability or mitochondrial dysfunction. These results show that concomitant exposure to NO and ROS impairs energy metabolism and triggers PARP-independent cell death. While superoxide-mediated PARP activation is attenuated in the presence of NO, PARP inhibition does not modify the loss of mitochondrial function or adenine and pyridine nucleotide pools and subsequent bioenergetic dysfunction. These findings suggest that the mechanisms by which ROS and NO induce endothelial cell death are closely linked to the maintenance of mitochondrial function and not overactivation of PARP.

Author List

Broniowska KA, Diers AR, Corbett JA, Hogg N

Authors

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin
Neil Hogg PhD Associate Dean, Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Aorta
Cattle
Cell Death
Cells, Cultured
Endothelium, Vascular
Energy Metabolism
Mitochondria
Naphthoquinones
Nitric Oxide
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases
Reactive Oxygen Species