Extracellular MicroRNA-92a Mediates Endothelial Cell-Macrophage Communication

Ya Ju Chang, Yi Shuan Li, Chia Ching Wu, Kuei Chun Wang, Tzu Chieh Huang, Zhen Chen, Shu Chien

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: Understanding message delivery among vascular cells is essential for deciphering the intercellular communications in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene KLF4 (Krüppel-like factor 4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a-induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases. CONCLUSIONS: EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.

Original languageEnglish
Pages (from-to)2492-2504
Number of pages13
JournalArteriosclerosis, thrombosis, and vascular biology
Volume39
Issue number12
DOIs
Publication statusPublished - 2019 Dec 1

Fingerprint

MicroRNAs
Cell Communication
Endothelial Cells
Macrophages
Phenotype
Conditioned Culture Medium
Serum
Vascular Diseases
LDL Lipoproteins
Blood Vessels
Cardiovascular Diseases
Gene Expression

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Chang, Ya Ju ; Li, Yi Shuan ; Wu, Chia Ching ; Wang, Kuei Chun ; Huang, Tzu Chieh ; Chen, Zhen ; Chien, Shu. / Extracellular MicroRNA-92a Mediates Endothelial Cell-Macrophage Communication. In: Arteriosclerosis, thrombosis, and vascular biology. 2019 ; Vol. 39, No. 12. pp. 2492-2504.
@article{965f20e41b7a46bfbf12aed6ac811bdf,
title = "Extracellular MicroRNA-92a Mediates Endothelial Cell-Macrophage Communication",
abstract = "OBJECTIVE: Understanding message delivery among vascular cells is essential for deciphering the intercellular communications in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene KLF4 (Kr{\"u}ppel-like factor 4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a-induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases. CONCLUSIONS: EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.",
author = "Chang, {Ya Ju} and Li, {Yi Shuan} and Wu, {Chia Ching} and Wang, {Kuei Chun} and Huang, {Tzu Chieh} and Zhen Chen and Shu Chien",
year = "2019",
month = "12",
day = "1",
doi = "10.1161/ATVBAHA.119.312707",
language = "English",
volume = "39",
pages = "2492--2504",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

Extracellular MicroRNA-92a Mediates Endothelial Cell-Macrophage Communication. / Chang, Ya Ju; Li, Yi Shuan; Wu, Chia Ching; Wang, Kuei Chun; Huang, Tzu Chieh; Chen, Zhen; Chien, Shu.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 39, No. 12, 01.12.2019, p. 2492-2504.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Extracellular MicroRNA-92a Mediates Endothelial Cell-Macrophage Communication

AU - Chang, Ya Ju

AU - Li, Yi Shuan

AU - Wu, Chia Ching

AU - Wang, Kuei Chun

AU - Huang, Tzu Chieh

AU - Chen, Zhen

AU - Chien, Shu

PY - 2019/12/1

Y1 - 2019/12/1

N2 - OBJECTIVE: Understanding message delivery among vascular cells is essential for deciphering the intercellular communications in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene KLF4 (Krüppel-like factor 4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a-induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases. CONCLUSIONS: EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.

AB - OBJECTIVE: Understanding message delivery among vascular cells is essential for deciphering the intercellular communications in cardiovascular diseases. MicroRNA (miR)-92a is enriched in endothelial cells (ECs) and circulation under atheroprone conditions. Macrophages are the primary immune cells in atherosclerotic lesions that modulate lesion development. Therefore, we hypothesize that, in response to atheroprone stimuli, ECs export miR-92a to macrophages to regulate their functions and enhance atherosclerotic progression. Approach and Results: We investigated the macrophage functions that are regulated by EC miR-92a under atheroprone microenvironments. We first determined the distributions of functional extracellular miR-92a by fractionating the intravesicular and extravesicular compartments from endothelial conditioned media and mice serum. The results indicate that extracellular vesicles are the primary vehicles for EC miR-92a transportation. Overexpression of miR-92a in ECs enhanced the proinflammatory responses and low-density lipoprotein uptake, while impaired the migration, of cocultured macrophage. Opposite effects were found in macrophages cocultured with ECs with miR-92a knockdown. Further analyses demonstrated that intravesicular miR-92a suppressed the expression of target gene KLF4 (Krüppel-like factor 4) in macrophages, suggesting a mechanism by which intravesicular miR-92a regulates recipient cell functions. Indeed, the overexpression of KLF4 rescued the EC miR-92a-induced macrophage atheroprone phenotypes. Furthermore, an inverse correlation of intravesicular miR-92a in blood serum and KLF4 expression in lesions was observed in atherosclerotic animals, indicating the potential function of extracellular miR-92a in regulating vascular diseases. CONCLUSIONS: EC miR-92a can be transported to macrophages through extracellular vesicles to regulate KLF4 levels, thus leading to the atheroprone phenotypes of macrophage and, hence, atherosclerotic lesion formation.

UR - http://www.scopus.com/inward/record.url?scp=85075814748&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075814748&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.119.312707

DO - 10.1161/ATVBAHA.119.312707

M3 - Article

C2 - 31597449

AN - SCOPUS:85075814748

VL - 39

SP - 2492

EP - 2504

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 12

ER -