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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • February 2022

Published In

Volume / Issue

  • 29 / 2

Start / End Page

  • 281 - 297.e12

PubMed ID

  • 34762860

Pubmed Central ID

  • PMC9021927

Electronic International Standard Serial Number (EISSN)

  • 1875-9777

International Standard Serial Number (ISSN)

  • 1934-5909

Digital Object Identifier (DOI)

  • 10.1016/j.stem.2021.10.009


  • eng