|Title||Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||V Janbandhu, V Tallapragada, R Patrick, Y Li, D Abeygunawardena, DT Humphreys, EMMA Martin, AO Ward, O Contreras, N Farbehi, E Yao, J Du, SL Dunwoodie, N Bursac, and RP Harvey|
|Journal||Cell Stem Cell|
|Pagination||281 - 297.e12|
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.
|Short Title||Cell Stem Cell|