TY - JOUR
T1 - Egr-1 mediates leptin-induced PPARγ reduction and proliferation of pulmonary artery smooth muscle cells
AU - Xie, Xinming
AU - Li, Shaojun
AU - Zhu, Yanting
AU - Liu, Lu
AU - Ke, Rui
AU - Wang, Jian
AU - Yan, Xin
AU - Yang, Lan
AU - Gao, Li
AU - Zang, Weijin
AU - Li, Manxiang
N1 - Funding Information:
This study was supported by the National Natural Science Foundation of China (Grant No. 81330002).
Publisher Copyright:
© 2018 Xie et al.
PY - 2018/2/1
Y1 - 2018/2/1
N2 - Loss of peroxisome proliferator-activated receptor γ (PPARγ) has been found to contribute to pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary arterial remodeling therefore the development of pulmonary hypertension (PH). Yet, the molecular mechanisms underlying PPARγ reduction in PASMC remain poorly understood. Here, we demonstrated that leptin dose- and time-dependently inducued PPARγ down-regulation and proliferation of primary cultured rat PASMC, this was accompanied with the activation of extracellular regulated kinase1/2 (ERK1/2) signaling pathway and subsequent induction of early growth response-1 (Egr-1) expression. The presence of MEK inhibitors U0126 or PD98059, or prior silencing Egr-1 with small interfering RNA suppressed leptin-induced PPARγ reduction. In addition, activation of PPARγ by pioglitazone or targeting ERK1/2/Egr-1 suppressed leptin-induced PASMC proliferation. Taken together, our study indicates that ERK1/2 signaling pathway-mediated leptin-induced PPARγ reduction and PASMC proliferation through up-regulation of Egr-1 and suggests that targeting leptin/ERK1/2/Egr-1 pathway might have potential value in ameliorating vascular remodeling and benefit PH.
AB - Loss of peroxisome proliferator-activated receptor γ (PPARγ) has been found to contribute to pulmonary artery smooth muscle cell (PASMC) proliferation and pulmonary arterial remodeling therefore the development of pulmonary hypertension (PH). Yet, the molecular mechanisms underlying PPARγ reduction in PASMC remain poorly understood. Here, we demonstrated that leptin dose- and time-dependently inducued PPARγ down-regulation and proliferation of primary cultured rat PASMC, this was accompanied with the activation of extracellular regulated kinase1/2 (ERK1/2) signaling pathway and subsequent induction of early growth response-1 (Egr-1) expression. The presence of MEK inhibitors U0126 or PD98059, or prior silencing Egr-1 with small interfering RNA suppressed leptin-induced PPARγ reduction. In addition, activation of PPARγ by pioglitazone or targeting ERK1/2/Egr-1 suppressed leptin-induced PASMC proliferation. Taken together, our study indicates that ERK1/2 signaling pathway-mediated leptin-induced PPARγ reduction and PASMC proliferation through up-regulation of Egr-1 and suggests that targeting leptin/ERK1/2/Egr-1 pathway might have potential value in ameliorating vascular remodeling and benefit PH.
UR - http://www.scopus.com/inward/record.url?scp=85041440089&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041440089&partnerID=8YFLogxK
U2 - 10.1091/mbc.E17-03-0141
DO - 10.1091/mbc.E17-03-0141
M3 - Article
C2 - 29212876
AN - SCOPUS:85041440089
SN - 1059-1524
VL - 29
SP - 356
EP - 362
JO - Molecular biology of the cell
JF - Molecular biology of the cell
IS - 3
ER -