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

Janbandhu, Vaibhao and Tallapragada, Vikram and Patrick, Ralph and Li, Yanzhen and Abeygunawardena, Dhanushi and Humphreys, David T. and Martin, Ella M.M.A. and Ward, Alexander O. and Contreras, Osvaldo and Farbehi, Nona and Yao, Ernestene and Du, Junjie and Dunwoodie, Sally L. and Bursac, Nenad and Harvey, Richard P. (2022) Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell Stem Cell, 29 (2). pp. 281-297.e12. ISSN 19345909

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Link to published document: http://doi.org/10.1016/j.stem.2021.10.009

Abstract

We report that cardiac fibroblasts (CFs) and mesenchymal progenitors are more hypoxic than other cardiac interstitial populations, express more hypoxia-inducible factor 1alpha (HIF-1alpha), 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 approximately 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-1alpha 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.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 14 Apr 2022 03:09
Last Modified: 14 Apr 2022 03:09
URI: http://eprints.victorchang.edu.au/id/eprint/1195

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