Mechanosensitive PPAP2B regulates endothelial responses to atherorelevant hemodynamic forces

Congqing Wu, Ru Ting Huang, Cheng Hsiang Kuo, Sandeep Kumar, Chan Woo Kim, Yen Chen Lin, Yen Ju Chen, Anna Birukova, Konstantin G. Birukov, Nickolai O. Dulin, Mete Civelek, Aldons J. Lusis, Xavier Loyer, Alain Tedgui, Guohao Dai, Hanjoong Jo, Yun Fang

研究成果: Article

35 引文 (Scopus)

摘要

Rationale: PhosPhatidic Acid Phosphatase type 2B (PPAP2B), an integral membrane protein known as lipid phosphate phosphatase (LPP3) that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genomewide association studies. However, it is unclear whether genome-wide association studies-identified coronary artery disease genes, including PPAP2B, participate in mechanotransduction mechanisms by which vascular endothelia respond to local atherorelevant hemodynamics that contribute to the regional nature of atherosclerosis. Objective: To establish the critical role of PPAP2B in endothelial responses to hemodynamics. Methods and Results: Reduced PPAP2B was detected in vivo in mouse and swine aortic arch (AA) endothelia exposed to chronic disturbed flow, and in mouse carotid artery endothelia subjected to surgically induced acute disturbed flow. In humans, PPAP2B was reduced in the downstream part of carotid plaques where low shear stress prevails. In culture, reduced PPAP2B was measured in human aortic endothelial cells under atherosusceptible waveform mimicking flow in human carotid sinus. Flow-sensitive microRNA-92a and transcription factor KLF2 were identified as upstream inhibitor and activator of endothelial PPAP2B, respectively. PPAP2B suppression abrogated atheroprotection of unidirectional flow; inhibition of lysophosphatidic acid receptor 1 restored the flow-dependent, anti-inflammatory phenotype in PPAP2B-deficient cells. PPAP2B inhibition resulted in myosin light-chain phosphorylation and intercellular gaps, which were abolished by lysophosphatidic acid receptor 1/2 inhibition. Expression quantitative trait locus mapping demonstrated PPAP2B coronary artery disease risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in human aortic endothelial cells. Conclusions: Atherorelevant flows dynamically modulate endothelial PPAP2B expression through miR-92a and KLF2. Mechanosensitive PPAP2B plays a critical role in promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under atheroprotective flow.

原文English
頁(從 - 到)e41-e53
期刊Circulation Research
117
發行號4
DOIs
出版狀態Published - 2015 七月 1

指紋

Phosphatidate Phosphatase
Hemodynamics
Lysophosphatidic Acid Receptors
Coronary Artery Disease
Endothelium
Anti-Inflammatory Agents
Endothelial Cells
Phenotype
Carotid Sinus
Myosin Light Chains
Quantitative Trait Loci
Genome-Wide Association Study

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

引用此文

Wu, Congqing ; Huang, Ru Ting ; Kuo, Cheng Hsiang ; Kumar, Sandeep ; Kim, Chan Woo ; Lin, Yen Chen ; Chen, Yen Ju ; Birukova, Anna ; Birukov, Konstantin G. ; Dulin, Nickolai O. ; Civelek, Mete ; Lusis, Aldons J. ; Loyer, Xavier ; Tedgui, Alain ; Dai, Guohao ; Jo, Hanjoong ; Fang, Yun. / Mechanosensitive PPAP2B regulates endothelial responses to atherorelevant hemodynamic forces. 於: Circulation Research. 2015 ; 卷 117, 編號 4. 頁 e41-e53.
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title = "Mechanosensitive PPAP2B regulates endothelial responses to atherorelevant hemodynamic forces",
abstract = "Rationale: PhosPhatidic Acid Phosphatase type 2B (PPAP2B), an integral membrane protein known as lipid phosphate phosphatase (LPP3) that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genomewide association studies. However, it is unclear whether genome-wide association studies-identified coronary artery disease genes, including PPAP2B, participate in mechanotransduction mechanisms by which vascular endothelia respond to local atherorelevant hemodynamics that contribute to the regional nature of atherosclerosis. Objective: To establish the critical role of PPAP2B in endothelial responses to hemodynamics. Methods and Results: Reduced PPAP2B was detected in vivo in mouse and swine aortic arch (AA) endothelia exposed to chronic disturbed flow, and in mouse carotid artery endothelia subjected to surgically induced acute disturbed flow. In humans, PPAP2B was reduced in the downstream part of carotid plaques where low shear stress prevails. In culture, reduced PPAP2B was measured in human aortic endothelial cells under atherosusceptible waveform mimicking flow in human carotid sinus. Flow-sensitive microRNA-92a and transcription factor KLF2 were identified as upstream inhibitor and activator of endothelial PPAP2B, respectively. PPAP2B suppression abrogated atheroprotection of unidirectional flow; inhibition of lysophosphatidic acid receptor 1 restored the flow-dependent, anti-inflammatory phenotype in PPAP2B-deficient cells. PPAP2B inhibition resulted in myosin light-chain phosphorylation and intercellular gaps, which were abolished by lysophosphatidic acid receptor 1/2 inhibition. Expression quantitative trait locus mapping demonstrated PPAP2B coronary artery disease risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in human aortic endothelial cells. Conclusions: Atherorelevant flows dynamically modulate endothelial PPAP2B expression through miR-92a and KLF2. Mechanosensitive PPAP2B plays a critical role in promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under atheroprotective flow.",
author = "Congqing Wu and Huang, {Ru Ting} and Kuo, {Cheng Hsiang} and Sandeep Kumar and Kim, {Chan Woo} and Lin, {Yen Chen} and Chen, {Yen Ju} and Anna Birukova and Birukov, {Konstantin G.} and Dulin, {Nickolai O.} and Mete Civelek and Lusis, {Aldons J.} and Xavier Loyer and Alain Tedgui and Guohao Dai and Hanjoong Jo and Yun Fang",
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Wu, C, Huang, RT, Kuo, CH, Kumar, S, Kim, CW, Lin, YC, Chen, YJ, Birukova, A, Birukov, KG, Dulin, NO, Civelek, M, Lusis, AJ, Loyer, X, Tedgui, A, Dai, G, Jo, H & Fang, Y 2015, 'Mechanosensitive PPAP2B regulates endothelial responses to atherorelevant hemodynamic forces', Circulation Research, 卷 117, 編號 4, 頁 e41-e53. https://doi.org/10.1161/CIRCRESAHA.117.306457

Mechanosensitive PPAP2B regulates endothelial responses to atherorelevant hemodynamic forces. / Wu, Congqing; Huang, Ru Ting; Kuo, Cheng Hsiang; Kumar, Sandeep; Kim, Chan Woo; Lin, Yen Chen; Chen, Yen Ju; Birukova, Anna; Birukov, Konstantin G.; Dulin, Nickolai O.; Civelek, Mete; Lusis, Aldons J.; Loyer, Xavier; Tedgui, Alain; Dai, Guohao; Jo, Hanjoong; Fang, Yun.

於: Circulation Research, 卷 117, 編號 4, 01.07.2015, p. e41-e53.

研究成果: Article

TY - JOUR

T1 - Mechanosensitive PPAP2B regulates endothelial responses to atherorelevant hemodynamic forces

AU - Wu, Congqing

AU - Huang, Ru Ting

AU - Kuo, Cheng Hsiang

AU - Kumar, Sandeep

AU - Kim, Chan Woo

AU - Lin, Yen Chen

AU - Chen, Yen Ju

AU - Birukova, Anna

AU - Birukov, Konstantin G.

AU - Dulin, Nickolai O.

AU - Civelek, Mete

AU - Lusis, Aldons J.

AU - Loyer, Xavier

AU - Tedgui, Alain

AU - Dai, Guohao

AU - Jo, Hanjoong

AU - Fang, Yun

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Rationale: PhosPhatidic Acid Phosphatase type 2B (PPAP2B), an integral membrane protein known as lipid phosphate phosphatase (LPP3) that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genomewide association studies. However, it is unclear whether genome-wide association studies-identified coronary artery disease genes, including PPAP2B, participate in mechanotransduction mechanisms by which vascular endothelia respond to local atherorelevant hemodynamics that contribute to the regional nature of atherosclerosis. Objective: To establish the critical role of PPAP2B in endothelial responses to hemodynamics. Methods and Results: Reduced PPAP2B was detected in vivo in mouse and swine aortic arch (AA) endothelia exposed to chronic disturbed flow, and in mouse carotid artery endothelia subjected to surgically induced acute disturbed flow. In humans, PPAP2B was reduced in the downstream part of carotid plaques where low shear stress prevails. In culture, reduced PPAP2B was measured in human aortic endothelial cells under atherosusceptible waveform mimicking flow in human carotid sinus. Flow-sensitive microRNA-92a and transcription factor KLF2 were identified as upstream inhibitor and activator of endothelial PPAP2B, respectively. PPAP2B suppression abrogated atheroprotection of unidirectional flow; inhibition of lysophosphatidic acid receptor 1 restored the flow-dependent, anti-inflammatory phenotype in PPAP2B-deficient cells. PPAP2B inhibition resulted in myosin light-chain phosphorylation and intercellular gaps, which were abolished by lysophosphatidic acid receptor 1/2 inhibition. Expression quantitative trait locus mapping demonstrated PPAP2B coronary artery disease risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in human aortic endothelial cells. Conclusions: Atherorelevant flows dynamically modulate endothelial PPAP2B expression through miR-92a and KLF2. Mechanosensitive PPAP2B plays a critical role in promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under atheroprotective flow.

AB - Rationale: PhosPhatidic Acid Phosphatase type 2B (PPAP2B), an integral membrane protein known as lipid phosphate phosphatase (LPP3) that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genomewide association studies. However, it is unclear whether genome-wide association studies-identified coronary artery disease genes, including PPAP2B, participate in mechanotransduction mechanisms by which vascular endothelia respond to local atherorelevant hemodynamics that contribute to the regional nature of atherosclerosis. Objective: To establish the critical role of PPAP2B in endothelial responses to hemodynamics. Methods and Results: Reduced PPAP2B was detected in vivo in mouse and swine aortic arch (AA) endothelia exposed to chronic disturbed flow, and in mouse carotid artery endothelia subjected to surgically induced acute disturbed flow. In humans, PPAP2B was reduced in the downstream part of carotid plaques where low shear stress prevails. In culture, reduced PPAP2B was measured in human aortic endothelial cells under atherosusceptible waveform mimicking flow in human carotid sinus. Flow-sensitive microRNA-92a and transcription factor KLF2 were identified as upstream inhibitor and activator of endothelial PPAP2B, respectively. PPAP2B suppression abrogated atheroprotection of unidirectional flow; inhibition of lysophosphatidic acid receptor 1 restored the flow-dependent, anti-inflammatory phenotype in PPAP2B-deficient cells. PPAP2B inhibition resulted in myosin light-chain phosphorylation and intercellular gaps, which were abolished by lysophosphatidic acid receptor 1/2 inhibition. Expression quantitative trait locus mapping demonstrated PPAP2B coronary artery disease risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in human aortic endothelial cells. Conclusions: Atherorelevant flows dynamically modulate endothelial PPAP2B expression through miR-92a and KLF2. Mechanosensitive PPAP2B plays a critical role in promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under atheroprotective flow.

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