Peroxisome proliferator-activated receptor γ inhibits pulmonary hypertension targeting store-operated calcium entry
UNLABELLED: 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.
KEY MESSAGES: 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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2015 |
|---|---|
| Erschienen: |
2015 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:93 |
|---|---|
| Enthalten in: |
Journal of molecular medicine (Berlin, Germany) - 93(2015), 3 vom: 13. März, Seite 327-42 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Wang, Yingfeng [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 14.03.2016 Date Revised 02.12.2018 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s00109-014-1216-4 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM243489730 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM243489730 | ||
| 003 | DE-627 | ||
| 005 | 20231224132634.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231224s2015 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s00109-014-1216-4 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0811.xml |
| 035 | |a (DE-627)NLM243489730 | ||
| 035 | |a (NLM)25391250 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Wang, Yingfeng |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Peroxisome proliferator-activated receptor γ inhibits pulmonary hypertension targeting store-operated calcium entry |
| 264 | 1 | |c 2015 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 14.03.2016 | ||
| 500 | |a Date Revised 02.12.2018 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a UNLABELLED: 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 | ||
| 520 | |a KEY MESSAGES: 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Hif1a protein, rat |2 NLM | |
| 650 | 7 | |a Hypoxia-Inducible Factor 1, alpha Subunit |2 NLM | |
| 650 | 7 | |a PPAR gamma |2 NLM | |
| 650 | 7 | |a TRPC Cation Channels |2 NLM | |
| 650 | 7 | |a Thiazolidinediones |2 NLM | |
| 650 | 7 | |a Trpc6 protein, rat |2 NLM | |
| 650 | 7 | |a transient receptor potential cation channel, subfamily C, member 1 |2 NLM | |
| 650 | 7 | |a Rosiglitazone |2 NLM | |
| 650 | 7 | |a 05V02F2KDG |2 NLM | |
| 700 | 1 | |a Lu, Wenju |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Kai |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jie |e verfasserin |4 aut | |
| 700 | 1 | |a Jia, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Yun, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Tian, Lichun |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yuqin |e verfasserin |4 aut | |
| 700 | 1 | |a Jiang, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Bo |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xiuqing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jian |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of molecular medicine (Berlin, Germany) |d 1995 |g 93(2015), 3 vom: 13. März, Seite 327-42 |w (DE-627)NLM075191725 |x 1432-1440 |7 nnns |
| 773 | 1 | 8 | |g volume:93 |g year:2015 |g number:3 |g day:13 |g month:03 |g pages:327-42 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00109-014-1216-4 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 93 |j 2015 |e 3 |b 13 |c 03 |h 327-42 | ||