Negative regulation of NOD1 mediated angiogenesis by PPARγ-regulated miR-125a.
Infection with pathogens activates the endothelial cell and its sustained activation may result in impaired endothelial function. Endothelial dysfunction contributes to the pathologic angiogenesis that is characteristic of infection-induced inflammatory pathway activation. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a protein receptor which recognizes bacterial molecules and stimulates an immune reaction in various cells; however, the underlying molecular mechanisms in the regulation of inflammation-triggered angiogenesis are not fully understood. Here we report that peroxisome proliferator-activated receptor gamma (PPARγ)-mediated miR-125a serves as an important regulator of NOD1 agonist-mediated angiogenesis in endothelial cells by directly targeting NOD1. Treatment of human umbilical vein endothelial cells with natural PPARγ ligand, 15-Deoxy-Delta12,14-prostaglandin J2, led to inhibition of NOD1 expression; contrarily, protein levels of NOD1 were significantly increased by PPARγ knockdown. We report that PPARγ regulation of NOD1 expression is a novel microRNA-mediated regulation in endothelial cells. MiR-125a expression was markedly decreased in human umbilical vein endothelial cells subjected to PPARγ knockdown while 15-Deoxy-Delta12,14-prostaglandin J2 treatment increased the level of miR-125a. In addition, NOD1 is closely regulated by miR-125a, which directly targets the 3' untranslated region of NOD1. Moreover, both overexpression of miR-125a and PPARγ activation led to inhibition of NOD1 agonist-induced tube formation in endothelial cells. Finally, NOD1 agonist increased the formation of cranial and subintestinal vessel plexus in zebrafish, and this effect was abrogated by concurrent PPARγ activation. Overall, these findings identify a PPARγ-miR-125a-NOD1 signaling axis in endothelial cells that is critical in the regulation of inflammation-mediated angiogenesis.
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Hyesoo
H
Kang
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Youngsook
Y
Park
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Aram
A
Lee
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Hyemin
H
Seo
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Min Jung
MJ
Kim
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Jihea
J
Choi
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Ha-Neul
HN
Jo
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Ha-Neul
HN
Jeong
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Jin Gu
JG
Cho
Department of Biology Education, College of Education, Pusan National University, Busan, 46241, South Korea.
Woochul
W
Chang
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea.
Myeong-Sok
MS
Lee
Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, South Korea.
Raok
R
Jeon
Department of Life Systems, Sookmyung Women's University, Seoul, 04310, South Korea. Electronic address: jkim@sookmyung.ac.kr.
Jongmin
J
Kim
D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D014657:Vasculitis / Q000378:metabolism* / Q000473:pathology; D015027:Zebrafish
C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D047495:PPAR gamma
Angiogenesis; Endothelial cell; MicroRNA; Nucleotide-binding oligomerization domain-containing protein 1; Peroxisome proliferator-activated receptor gamma