Skip to main content
Duke University Libraries
DukeSpace Scholarship by Duke Authors
  • Login
  • Ask
  • Menu
  • Login
  • Ask a Librarian
  • Search & Find
  • Using the Library
  • Research Support
  • Course Support
  • Libraries
  • About
View Item 
  •   DukeSpace
  • Duke Scholarly Works
  • Scholarly Articles
  • View Item
  •   DukeSpace
  • Duke Scholarly Works
  • Scholarly Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy.

Thumbnail
View / Download
2.0 Mb
Date
2007-12
Authors
Suliman, Hagir B
Carraway, Martha Sue
Ali, Abdelwahid S
Reynolds, Chrystal M
Welty-Wolf, Karen E
Piantadosi, Claude A
Repository Usage Stats
134
views
111
downloads
Abstract
The clinical utility of anthracycline anticancer agents, especially doxorubicin, is limited by a progressive toxic cardiomyopathy linked to mitochondrial damage and cardiomyocyte apoptosis. Here we demonstrate that the post-doxorubicin mouse heart fails to upregulate the nuclear program for mitochondrial biogenesis and its associated intrinsic antiapoptosis proteins, leading to severe mitochondrial DNA (mtDNA) depletion, sarcomere destruction, apoptosis, necrosis, and excessive wall stress and fibrosis. Furthermore, we exploited recent evidence that mitochondrial biogenesis is regulated by the CO/heme oxygenase (CO/HO) system to ameliorate doxorubicin cardiomyopathy in mice. We found that the myocardial pathology was averted by periodic CO inhalation, which restored mitochondrial biogenesis and circumvented intrinsic apoptosis through caspase-3 and apoptosis-inducing factor. Moreover, CO simultaneously reversed doxorubicin-induced loss of DNA binding by GATA-4 and restored critical sarcomeric proteins. In isolated rat cardiac cells, HO-1 enzyme overexpression prevented doxorubicin-induced mtDNA depletion and apoptosis via activation of Akt1/PKB and guanylate cyclase, while HO-1 gene silencing exacerbated doxorubicin-induced mtDNA depletion and apoptosis. Thus doxorubicin disrupts cardiac mitochondrial biogenesis, which promotes intrinsic apoptosis, while CO/HO promotes mitochondrial biogenesis and opposes apoptosis, forestalling fibrosis and cardiomyopathy. These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis.
Type
Journal article
Subject
3-Phosphoinositide-Dependent Protein Kinases
Animals
Antibiotics, Antineoplastic
Antimetabolites
Apoptosis
Carbon Monoxide
Cardiomyopathies
Caspase 3
Cells, Cultured
DNA, Mitochondrial
Doxorubicin
Fibrosis
GATA4 Transcription Factor
Gene Silencing
Guanylate Cyclase
Heme Oxygenase (Decyclizing)
Male
Mice
Mitochondria, Heart
Myocardium
Necrosis
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins c-akt
Rats
Sarcomeres
Permalink
https://hdl.handle.net/10161/13989
Published Version (Please cite this version)
10.1172/JCI32967
Publication Info
Suliman, Hagir B; Carraway, Martha Sue; Ali, Abdelwahid S; Reynolds, Chrystal M; Welty-Wolf, Karen E; & Piantadosi, Claude A (2007). The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J Clin Invest, 117(12). pp. 3730-3741. 10.1172/JCI32967. Retrieved from https://hdl.handle.net/10161/13989.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
Collections
  • Scholarly Articles
More Info
Show full item record

Scholars@Duke

Piantadosi

Claude Anthony Piantadosi

Professor Emeritus of Medicine
Dr. Piantadosi's laboratory has special expertise in the pathogenic mechanisms of acute organ failure, particularly acute lung injury (ALI), with an emphasis on the molecular regulatory roles of the physiological gases— oxygen, carbon monoxide, and nitric oxide— as they relate to the damage responses to acute inflammation. The basic science focuses on oxidative processes and redox-regulation, especially the molecular mechanisms by which reactive oxygen and nitrogen species trans
Suliman

Hagir B. Suliman

Associate Professor in Anesthesiology
Dr. Suliman is an expert in the molecular and cell biology of mammalian diseases, particularly in the molecular regulation of oxidant inflammatory responses in the heart and lung. She has a strong interest and expertise in the transcriptional control of cell metabolism, especially mitochondrial biogenesis and mitochondrial-mediated apoptosis and necrosis. Her recent publications have focused on the redox-regulation of nuclear transcription factors involved in both mitochondrial biogenesis and
Welty-Wolf

Karen Elizabeth Welty-Wolf

Professor of Medicine
Dr. Welty-Wolf studies (1) pathophysiology and treatment of acute lung injury and (2) multiple organ failure and disordered energy metabolism in sepsis. Injury models include hyperoxic lung injury and ARDS with multiple organ failure due to sepsis. In addition to evaluating mechanisms of lung injury in sepsis, current studies are being conducted to evaluate the potential role of monoclinal antibodies to neutrophil adhesion molecules in the prevention of this injury. Other sepsis work inc
Alphabetical list of authors with Scholars@Duke profiles.
Open Access

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy

Rights for Collection: Scholarly Articles


Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info

Make Your Work Available Here

How to Deposit

Browse

All of DukeSpaceCommunities & CollectionsAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit DateThis CollectionAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit Date

My Account

LoginRegister

Statistics

View Usage Statistics
Duke University Libraries

Contact Us

411 Chapel Drive
Durham, NC 27708
(919) 660-5870
Perkins Library Service Desk

Digital Repositories at Duke

  • Report a problem with the repositories
  • About digital repositories at Duke
  • Accessibility Policy
  • Deaccession and DMCA Takedown Policy

TwitterFacebookYouTubeFlickrInstagramBlogs

Sign Up for Our Newsletter
  • Re-use & Attribution / Privacy
  • Harmful Language Statement
  • Support the Libraries
Duke University