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A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells
Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198948/ https://www.ncbi.nlm.nih.gov/pubmed/35695893 http://dx.doi.org/10.1083/jcb.202109144 |
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author | Coon, Brian G. Timalsina, Sushma Astone, Matteo Zhuang, Zhen W. Fang, Jennifer Han, Jinah Themen, Jurgen Chung, Minhwan Yang-Klingler, Young Joo Jain, Mukesh Hirschi, Karen K. Yamamato, Ai Trudeau, Louis-Eric Santoro, Massimo Schwartz, Martin A. |
author_facet | Coon, Brian G. Timalsina, Sushma Astone, Matteo Zhuang, Zhen W. Fang, Jennifer Han, Jinah Themen, Jurgen Chung, Minhwan Yang-Klingler, Young Joo Jain, Mukesh Hirschi, Karen K. Yamamato, Ai Trudeau, Louis-Eric Santoro, Massimo Schwartz, Martin A. |
author_sort | Coon, Brian G. |
collection | PubMed |
description | Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction of the anti-inflammatory transcription factor, Kruppel-like factor 2 (Klf2). We therefore performed a whole genome CRISPR-Cas9 screen to identify genes required for LSS induction of Klf2. Subsequent mechanistic investigation revealed that LSS induces Klf2 via activation of both a MEKK2/3–MEK5–ERK5 kinase module and mitochondrial metabolism. Mitochondrial calcium and ROS signaling regulate assembly of a mitophagy- and p62-dependent scaffolding complex that amplifies MEKK–MEK5–ERK5 signaling. Blocking the mitochondrial pathway in vivo reduces expression of KLF2-dependent genes such as eNOS and inhibits vascular remodeling. Failure to activate the mitochondrial pathway limits Klf2 expression in regions of disturbed flow. This work thus defines a connection between metabolism and vascular inflammation that provides a new framework for understanding and developing treatments for vascular disease. |
format | Online Article Text |
id | pubmed-9198948 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-91989482023-01-04 A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells Coon, Brian G. Timalsina, Sushma Astone, Matteo Zhuang, Zhen W. Fang, Jennifer Han, Jinah Themen, Jurgen Chung, Minhwan Yang-Klingler, Young Joo Jain, Mukesh Hirschi, Karen K. Yamamato, Ai Trudeau, Louis-Eric Santoro, Massimo Schwartz, Martin A. J Cell Biol Article Atherosclerosis, the major cause of myocardial infarction and stroke, results from converging inflammatory, metabolic, and biomechanical factors. Arterial lesions form at sites of low and disturbed blood flow but are suppressed by high laminar shear stress (LSS) mainly via transcriptional induction of the anti-inflammatory transcription factor, Kruppel-like factor 2 (Klf2). We therefore performed a whole genome CRISPR-Cas9 screen to identify genes required for LSS induction of Klf2. Subsequent mechanistic investigation revealed that LSS induces Klf2 via activation of both a MEKK2/3–MEK5–ERK5 kinase module and mitochondrial metabolism. Mitochondrial calcium and ROS signaling regulate assembly of a mitophagy- and p62-dependent scaffolding complex that amplifies MEKK–MEK5–ERK5 signaling. Blocking the mitochondrial pathway in vivo reduces expression of KLF2-dependent genes such as eNOS and inhibits vascular remodeling. Failure to activate the mitochondrial pathway limits Klf2 expression in regions of disturbed flow. This work thus defines a connection between metabolism and vascular inflammation that provides a new framework for understanding and developing treatments for vascular disease. Rockefeller University Press 2022-06-13 /pmc/articles/PMC9198948/ /pubmed/35695893 http://dx.doi.org/10.1083/jcb.202109144 Text en © 2022 Coon et al. https://creativecommons.org/licenses/by-nc-sa/4.0/http://www.rupress.org/terms/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Coon, Brian G. Timalsina, Sushma Astone, Matteo Zhuang, Zhen W. Fang, Jennifer Han, Jinah Themen, Jurgen Chung, Minhwan Yang-Klingler, Young Joo Jain, Mukesh Hirschi, Karen K. Yamamato, Ai Trudeau, Louis-Eric Santoro, Massimo Schwartz, Martin A. A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells |
title | A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells |
title_full | A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells |
title_fullStr | A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells |
title_full_unstemmed | A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells |
title_short | A mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells |
title_sort | mitochondrial contribution to anti-inflammatory shear stress signaling in vascular endothelial cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9198948/ https://www.ncbi.nlm.nih.gov/pubmed/35695893 http://dx.doi.org/10.1083/jcb.202109144 |
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