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Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction.

Publication ,  Journal Article
Janbandhu, V; Tallapragada, V; Patrick, R; Li, Y; Abeygunawardena, D; Humphreys, DT; Martin, EMMA; Ward, AO; Contreras, O; Farbehi, N; Yao, E ...
Published in: Cell stem cell
February 2022

We report that cardiac fibroblasts (CFs) and mesenchymal progenitors are more hypoxic than other cardiac interstitial populations, express more hypoxia-inducible factor 1α (HIF-1α), and exhibit increased glycolytic metabolism. CF-specific deletion of Hif-1a resulted in decreased HIF-1 target gene expression and increased mesenchymal progenitors in uninjured hearts and increased CF activation without proliferation following sham injury, as demonstrated using single-cell RNA sequencing (scRNA-seq). After myocardial infarction (MI), however, there was ∼50% increased CF proliferation and excessive scarring and contractile dysfunction, a scenario replicated in 3D engineered cardiac microtissues. CF proliferation was associated with higher reactive oxygen species (ROS) as occurred also in wild-type mice treated with the mitochondrial ROS generator MitoParaquat (MitoPQ). The mitochondrial-targeted antioxidant MitoTEMPO rescued Hif-1a mutant phenotypes. Thus, HIF-1α in CFs provides a critical braking mechanism against excessive post-ischemic CF activation and proliferation through regulation of mitochondrial ROS. CFs are potential cellular targets for designer antioxidant therapies in cardiovascular disease.

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Published In

Cell stem cell

DOI

EISSN

1875-9777

ISSN

1934-5909

Publication Date

February 2022

Volume

29

Issue

2

Start / End Page

281 / 297.e12

Related Subject Headings

  • Reactive Oxygen Species
  • Myocardial Infarction
  • Mice
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Fibroblasts
  • Developmental Biology
  • Cell Proliferation
  • Antioxidants
  • Animals
  • 32 Biomedical and clinical sciences
 

Citation

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Janbandhu, V., Tallapragada, V., Patrick, R., Li, Y., Abeygunawardena, D., Humphreys, D. T., … Harvey, R. P. (2022). Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell Stem Cell, 29(2), 281-297.e12. https://doi.org/10.1016/j.stem.2021.10.009
Janbandhu, Vaibhao, Vikram Tallapragada, Ralph Patrick, Yanzhen Li, Dhanushi Abeygunawardena, David T. Humphreys, Ella M. M. A. Martin, et al. “Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction.Cell Stem Cell 29, no. 2 (February 2022): 281-297.e12. https://doi.org/10.1016/j.stem.2021.10.009.
Janbandhu V, Tallapragada V, Patrick R, Li Y, Abeygunawardena D, Humphreys DT, et al. Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell stem cell. 2022 Feb;29(2):281-297.e12.
Janbandhu, Vaibhao, et al. “Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction.Cell Stem Cell, vol. 29, no. 2, Feb. 2022, pp. 281-297.e12. Epmc, doi:10.1016/j.stem.2021.10.009.
Janbandhu V, Tallapragada V, Patrick R, Li Y, Abeygunawardena D, Humphreys DT, Martin EMMA, Ward AO, Contreras O, Farbehi N, Yao E, Du J, Dunwoodie SL, Bursac N, Harvey RP. Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell stem cell. 2022 Feb;29(2):281-297.e12.
Journal cover image

Published In

Cell stem cell

DOI

EISSN

1875-9777

ISSN

1934-5909

Publication Date

February 2022

Volume

29

Issue

2

Start / End Page

281 / 297.e12

Related Subject Headings

  • Reactive Oxygen Species
  • Myocardial Infarction
  • Mice
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Fibroblasts
  • Developmental Biology
  • Cell Proliferation
  • Antioxidants
  • Animals
  • 32 Biomedical and clinical sciences