PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1
| Autor: | Cynthia St. Hilaire, John F. Keaney, Hyung-Jin Yoo, Juan M. Jiménez, Joshua D. Hall, Siobhan M. Craige, Swenja Kröller-Schön, Eberhard Schulz, Khanh-Van Tran, Amada D. Caliz, Ana C. Dolan, Miroslava Kvandova, Heather Learnard, Shashi Kant |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
HMOX1 Epithelial-Mesenchymal Transition Endothelium Mechanotransduction Cellular Article Gene Expression Regulation Enzymologic chemistry.chemical_compound In vivo medicine Human Umbilical Vein Endothelial Cells Animals Humans Telomerase reverse transcriptase Receptor Heme Telomerase Cells Cultured Mice Knockout Endothelial Cells Membrane Proteins Laminar flow Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Cell biology Heme oxygenase Mice Inbred C57BL medicine.anatomical_structure chemistry Regional Blood Flow Female Stress Mechanical Cardiology and Cardiovascular Medicine Heme Oxygenase-1 |
| Zdroj: | Arterioscler Thromb Vasc Biol |
| Popis: | Objective: Fluid shear stress (FSS) is known to mediate multiple phenotypic changes in the endothelium. Laminar FSS (undisturbed flow) is known to promote endothelial alignment to flow, which is key to stabilizing the endothelium and rendering it resistant to atherosclerosis and thrombosis. The molecular pathways responsible for endothelial responses to FSS are only partially understood. In this study, we determine the role of PGC1α (peroxisome proliferator gamma coactivator-1α)-TERT (telomerase reverse transcriptase)-HMOX1 (heme oxygenase-1) during shear stress in vitro and in vivo. Approach and Results: Here, we have identified PGC1α as a flow-responsive gene required for endothelial flow alignment in vitro and in vivo. Compared with oscillatory FSS (disturbed flow) or static conditions, laminar FSS (undisturbed flow) showed increased PGC1α expression and its transcriptional coactivation. PGC1α was required for laminar FSS-induced expression of TERT in vitro and in vivo via its association with ERRα(estrogen-related receptor alpha) and KLF (Kruppel-like factor)-4 on the TERT promoter. We found that TERT inhibition attenuated endothelial flow alignment, elongation, and nuclear polarization in response to laminar FSS in vitro and in vivo. Among the flow-responsive genes sensitive to TERT status, HMOX1 was required for endothelial alignment to laminar FSS. Conclusions: These data suggest an important role for a PGC1α-TERT-HMOX1 axis in the endothelial stabilization response to laminar FSS. |
| Databáze: | OpenAIRE |
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