Peroxisome proliferator-activated receptor γ inhibits pulmonary hypertension targeting store-operated calcium entry.
In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) on store-operated calcium entry (SOCE) and expression of the main store-operated calcium channel (SOCCs) components, canonical transient receptor potential (TRPC) in chronic hypoxia (CH)-induced pulmonary hypertension (CHPH) rat models. Small interfering RNA (siRNA) knockdown and adenoviral overexpression strategies were constructed for loss-of-function and gain-of-function experiments. PPARγ agonist rosiglitazone attenuates the pathogenesis of CHPH and suppresses Hif-1α, TRPC1, TRPC6 expression in the distal pulmonary arteries (PA), and SOCE in freshly isolated rat distal pulmonary arterial smooth muscle cells (PASMCs). By comprehensive use of knockdown and overexpression studies, and bioinformatical analysis of the TRPC gene promoter and luciferase reporter assay, we demonstrated that PPARγ exerts roles of anti-proliferation, anti-migration, and pro-apoptosis in PASMCs, likely by inhibiting the elevated SOCE and TRPC expression. These effects were inhibited under the conditions of hypoxia or Hif-1α accumulation. We also found that under hypoxia, accumulated Hif-1α protein acts as upstream of suppressed PPARγ level; however, targeted PPARγ rescue acts as negative feedback on suppressing Hif-1α level and Hif-1α mediated signaling pathway. PPARγ inhibits CHPH by targeting SOCE and TRPC via inhibiting Hif-1α expression and signaling transduction.


CONCLUSIONS
Rosiglitazone protects PH by normalizing RVSP but not right ventricle hypotrophy. PPARγ inhibits PASMCs proliferation via targeting SOCE and TRPC by suppressing Hif-1α. PPARγ and Hif-1α share mutual inhibitory regulation in PASMCs. PPARγ restoration might be a beneficial strategy for PH treatment.
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, 151 Yanjiang Road, Guangzhou, Guangdong, 510120, People's Republic of China.
Yingfeng
Y
Wang
Wenju
W
Lu
Kai
K
Yang
Yan
Y
Wang
Jie
J
Zhang
Jing
J
Jia
Xin
X
Yun
Lichun
L
Tian
Yuqin
Y
Chen
Qian
Q
Jiang
Bo
B
Zhang
Xiuqing
X
Chen
Jian
J
Wang
D000818:Animals; D020013:Calcium Signaling; D015687:Cell Hypoxia; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D006976:Hypertension, Pulmonary / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000502:physiology*; D011401:Promoter Regions, Genetic; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014158:Transcription, Genetic; D015533:Transcriptional Activation
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047495:PPAR gamma; D050052:TRPC Cation Channels; D045162:Thiazolidinediones; C492145:Trpc6 protein, rat; C096351:transient receptor potential cation channel, subfamily C, member 1; D000077154:Rosiglitazone