Cargando…

Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment

Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen—Lysyl oxidase-like 2 (Loxl2)—is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress...

Descripción completa

Detalles Bibliográficos
Autores principales: Yang, Jin, Savvatis, Konstantinos, Kang, Jong Seok, Fan, Peidong, Zhong, Hongyan, Schwartz, Karen, Barry, Vivian, Mikels-Vigdal, Amanda, Karpinski, Serge, Kornyeyev, Dmytro, Adamkewicz, Joanne, Feng, Xuhui, Zhou, Qiong, Shang, Ching, Kumar, Praveen, Phan, Dillon, Kasner, Mario, López, Begoña, Diez, Javier, Wright, Keith C., Kovacs, Roxanne L., Chen, Peng-Sheng, Quertermous, Thomas, Smith, Victoria, Yao, Lina, Tschöpe, Carsten, Chang, Ching-Pin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171850/
https://www.ncbi.nlm.nih.gov/pubmed/27966531
http://dx.doi.org/10.1038/ncomms13710
_version_ 1782484025316737024
author Yang, Jin
Savvatis, Konstantinos
Kang, Jong Seok
Fan, Peidong
Zhong, Hongyan
Schwartz, Karen
Barry, Vivian
Mikels-Vigdal, Amanda
Karpinski, Serge
Kornyeyev, Dmytro
Adamkewicz, Joanne
Feng, Xuhui
Zhou, Qiong
Shang, Ching
Kumar, Praveen
Phan, Dillon
Kasner, Mario
López, Begoña
Diez, Javier
Wright, Keith C.
Kovacs, Roxanne L.
Chen, Peng-Sheng
Quertermous, Thomas
Smith, Victoria
Yao, Lina
Tschöpe, Carsten
Chang, Ching-Pin
author_facet Yang, Jin
Savvatis, Konstantinos
Kang, Jong Seok
Fan, Peidong
Zhong, Hongyan
Schwartz, Karen
Barry, Vivian
Mikels-Vigdal, Amanda
Karpinski, Serge
Kornyeyev, Dmytro
Adamkewicz, Joanne
Feng, Xuhui
Zhou, Qiong
Shang, Ching
Kumar, Praveen
Phan, Dillon
Kasner, Mario
López, Begoña
Diez, Javier
Wright, Keith C.
Kovacs, Roxanne L.
Chen, Peng-Sheng
Quertermous, Thomas
Smith, Victoria
Yao, Lina
Tschöpe, Carsten
Chang, Ching-Pin
author_sort Yang, Jin
collection PubMed
description Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen—Lysyl oxidase-like 2 (Loxl2)—is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF.
format Online
Article
Text
id pubmed-5171850
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Nature Publishing Group
record_format MEDLINE/PubMed
spelling pubmed-51718502016-12-23 Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment Yang, Jin Savvatis, Konstantinos Kang, Jong Seok Fan, Peidong Zhong, Hongyan Schwartz, Karen Barry, Vivian Mikels-Vigdal, Amanda Karpinski, Serge Kornyeyev, Dmytro Adamkewicz, Joanne Feng, Xuhui Zhou, Qiong Shang, Ching Kumar, Praveen Phan, Dillon Kasner, Mario López, Begoña Diez, Javier Wright, Keith C. Kovacs, Roxanne L. Chen, Peng-Sheng Quertermous, Thomas Smith, Victoria Yao, Lina Tschöpe, Carsten Chang, Ching-Pin Nat Commun Article Interstitial fibrosis plays a key role in the development and progression of heart failure. Here, we show that an enzyme that crosslinks collagen—Lysyl oxidase-like 2 (Loxl2)—is essential for interstitial fibrosis and mechanical dysfunction of pathologically stressed hearts. In mice, cardiac stress activates fibroblasts to express and secrete Loxl2 into the interstitium, triggering fibrosis, systolic and diastolic dysfunction of stressed hearts. Antibody-mediated inhibition or genetic disruption of Loxl2 greatly reduces stress-induced cardiac fibrosis and chamber dilatation, improving systolic and diastolic functions. Loxl2 stimulates cardiac fibroblasts through PI3K/AKT to produce TGF-β2, promoting fibroblast-to-myofibroblast transformation; Loxl2 also acts downstream of TGF-β2 to stimulate myofibroblast migration. In diseased human hearts, LOXL2 is upregulated in cardiac interstitium; its levels correlate with collagen crosslinking and cardiac dysfunction. LOXL2 is also elevated in the serum of heart failure (HF) patients, correlating with other HF biomarkers, suggesting a conserved LOXL2-mediated mechanism of human HF. Nature Publishing Group 2016-12-14 /pmc/articles/PMC5171850/ /pubmed/27966531 http://dx.doi.org/10.1038/ncomms13710 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Yang, Jin
Savvatis, Konstantinos
Kang, Jong Seok
Fan, Peidong
Zhong, Hongyan
Schwartz, Karen
Barry, Vivian
Mikels-Vigdal, Amanda
Karpinski, Serge
Kornyeyev, Dmytro
Adamkewicz, Joanne
Feng, Xuhui
Zhou, Qiong
Shang, Ching
Kumar, Praveen
Phan, Dillon
Kasner, Mario
López, Begoña
Diez, Javier
Wright, Keith C.
Kovacs, Roxanne L.
Chen, Peng-Sheng
Quertermous, Thomas
Smith, Victoria
Yao, Lina
Tschöpe, Carsten
Chang, Ching-Pin
Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
title Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
title_full Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
title_fullStr Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
title_full_unstemmed Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
title_short Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment
title_sort targeting loxl2 for cardiac interstitial fibrosis and heart failure treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5171850/
https://www.ncbi.nlm.nih.gov/pubmed/27966531
http://dx.doi.org/10.1038/ncomms13710
work_keys_str_mv AT yangjin targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT savvatiskonstantinos targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT kangjongseok targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT fanpeidong targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT zhonghongyan targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT schwartzkaren targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT barryvivian targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT mikelsvigdalamanda targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT karpinskiserge targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT kornyeyevdmytro targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT adamkewiczjoanne targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT fengxuhui targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT zhouqiong targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT shangching targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT kumarpraveen targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT phandillon targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT kasnermario targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT lopezbegona targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT diezjavier targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT wrightkeithc targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT kovacsroxannel targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT chenpengsheng targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT quertermousthomas targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT smithvictoria targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT yaolina targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT tschopecarsten targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment
AT changchingpin targetingloxl2forcardiacinterstitialfibrosisandheartfailuretreatment