Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
Heme oxygenase-1 regulates mitochondrial quality control in the heart
Travis D. Hull, … , Anupam Agarwal, James F. George
Travis D. Hull, … , Anupam Agarwal, James F. George
Published February 25, 2016
Citation Information: JCI Insight. 2016;1(2):e85817. https://doi.org/10.1172/jci.insight.85817.
View: Text | PDF
Research Article Cardiology Cell biology

Heme oxygenase-1 regulates mitochondrial quality control in the heart

  • Text
  • PDF
Abstract

The cardioprotective inducible enzyme heme oxygenase-1 (HO-1) degrades prooxidant heme into equimolar quantities of carbon monoxide, biliverdin, and iron. We hypothesized that HO-1 mediates cardiac protection, at least in part, by regulating mitochondrial quality control. We treated WT and HO-1 transgenic mice with the known mitochondrial toxin, doxorubicin (DOX). Relative to WT mice, mice globally overexpressing human HO-1 were protected from DOX-induced dilated cardiomyopathy, cardiac cytoarchitectural derangement, and infiltration of CD11b+ mononuclear phagocytes. Cardiac-specific overexpression of HO-1 ameliorated DOX-mediated dilation of the sarcoplasmic reticulum as well as mitochondrial disorganization in the form of mitochondrial fragmentation and increased numbers of damaged mitochondria in autophagic vacuoles. HO-1 overexpression promotes mitochondrial biogenesis by upregulating protein expression of NRF1, PGC1α, and TFAM, which was inhibited in WT animals treated with DOX. Concomitantly, HO-1 overexpression inhibited the upregulation of the mitochondrial fission mediator Fis1 and resulted in increased expression of the fusion mediators, Mfn1 and Mfn2. It also prevented dynamic changes in the levels of key mediators of the mitophagy pathway, PINK1 and parkin. Therefore, these findings suggest that HO-1 has a novel role in protecting the heart from oxidative injury by regulating mitochondrial quality control.

Authors

Travis D. Hull, Ravindra Boddu, Lingling Guo, Cornelia C. Tisher, Amie M. Traylor, Bindiya Patel, Reny Joseph, Sumanth D. Prabhu, Hagir B. Suliman, Claude A. Piantadosi, Anupam Agarwal, James F. George

×

Figure 1

Heme oxygenase-1 overexpression prevents doxorubicin-induced cardiac toxicity.

Options: View larger image (or click on image) Download as PowerPoint
Heme oxygenase-1 overexpression prevents doxorubicin-induced cardiac tox...
(A) Schematic of the treatment protocol utilized in this study. Mice were administered three 6.0 mg/kg doses of intravenous doxorubicin (DOX) every third day for a week and euthanized for tissue collection. To assess cardiac function, mice underwent serial echocardiography the day before DOX administration and up to 14 days after treatment. (B) Heme oxygenase-1 (HO-1) overexpression in humanized HO-1 overexpressing (HBAC) mice was confirmed by Western blot on tissue lysates generated from the left ventricle (LV). GAPDH was used as a loading control. (C) Ejection fraction (EF), (D) end diastolic diameter (EDD), and (E) end systolic diameter (ESD) were measured by serial echocardiography. Black bars depict data from WT mice, white bars depict data from HBAC mice. Data are presented as mean ± SEM. *P < 0.05, 2-tailed paired t test was used to determine statistically significant changes after DOX treatment, relative to baseline values; n = 5–8 per group.

Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts