Peroxisome proliferator-activated receptor γ inhibits pulmonary hypertension targeting store-operated calcium entry

Yingfeng Wang, Wenju Lu, Kai Yang, Yan Wang, Jie Zhang, Jing Jia, Xin Yun, Lichun Tian, Yuqin Chen, Qian Jiang, Bo Zhang, Xiuqing Chen, Jian Wang

Research output: Contribution to journalArticle

Abstract

Abstract: 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.

Original languageEnglish (US)
Pages (from-to)327-342
Number of pages16
JournalJournal of Molecular Medicine
Volume93
Issue number3
DOIs
StatePublished - Feb 19 2015

Keywords

  • Hif-1α
  • PPARγ
  • Pulmonary hypertension
  • TRPC

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)

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  • Cite this

    Wang, Y., Lu, W., Yang, K., Wang, Y., Zhang, J., Jia, J., Yun, X., Tian, L., Chen, Y., Jiang, Q., Zhang, B., Chen, X., & Wang, J. (2015). Peroxisome proliferator-activated receptor γ inhibits pulmonary hypertension targeting store-operated calcium entry. Journal of Molecular Medicine, 93(3), 327-342. https://doi.org/10.1007/s00109-014-1216-4