PGC1α Regulates the Endothelial Response to Fluid Shear Stress via Telomerase Reverse Transcriptase Control of Heme Oxygenase-1.

Autor:	Kant S; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.K., A.D.C., H.-J.Y., A.C.D., J.F.K.)., Tran KV; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester (K.-V.T., H.L.)., Kvandova M; Department of Cardiology, University Medical Center, Mainz, Germany (M.K., S.K.-S.)., Caliz AD; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.K., A.D.C., H.-J.Y., A.C.D., J.F.K.)., Yoo HJ; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.K., A.D.C., H.-J.Y., A.C.D., J.F.K.)., Learnard H; Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester (K.-V.T., H.L.)., Dolan AC; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.K., A.D.C., H.-J.Y., A.C.D., J.F.K.)., Craige SM; Department of Human Nutrition, Foods, and Exercise, Virginia Tech, Blackburg, VA (S.M.C.)., Hall JD; Department of Mechanical and Industrial Engineering, University of Massachusetts, Amherst (J.D.H., J.M.J.)., Jiménez JM; Department of Mechanical and Industrial Engineering, University of Massachusetts, Amherst (J.D.H., J.M.J.)., St Hilaire C; Division of Cardiology, Departments of Medicine and Bioengineering, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, PA (C.S.H.)., Schulz E; Department of Cardiology, Allgemeines Krankenhaus, Celle, Germany (E.S.)., Kröller-Schön S; Department of Cardiology, University Medical Center, Mainz, Germany (M.K., S.K.-S.)., Keaney JF Jr; Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.K., A.D.C., H.-J.Y., A.C.D., J.F.K.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2022 Jan; Vol. 42 (1), pp. 19-34. Date of Electronic Publication: 2021 Nov 18.
DOI:	10.1161/ATVBAHA.121.317066
Abstrakt:	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:	MEDLINE
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