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

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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.

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Acknowledgments

We thank Drs. Qicai Liu and Bing Li for technical assistance and constructive discussion in this study.

Funding sources

This work was supported by NIH (R01-HL093020), National Natural Science Foundation of China (81173112, 81470246, 81170052, 81220108001), Guangdong Natural Science Foundation team (1035101200300000), Guangzhou Department of Education Yangcheng Scholarship (12A001S), Guangzhou Department of Natural Science (2014Y2-00167), and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2014, W Lu), China.

Conflict of interest

None.

Author contribution

JW initiated and designed the project, analyzed data, and wrote the paper; WL designed the project and edited the paper; YW performed the animal, functional, and molecular experiments; YW, JZ, XY, and JJ performed the molecular experiments; KY and LT edited the paper; YC, QJ, BZ, and XC performed the animal experiments.

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Authors and Affiliations

  1. 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 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

  2. Division of Pulmonary and Critical Care Medicine, School of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, Rm. 4B30, Baltimore, MD, 21224, USA

    Kai Yang, Xin Yun & Jian Wang

  3. Division of Pulmonary, The People’s Hospital of Inner Mongolia, Hohhot, Inner Mongolia, China

    Jian Wang

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  1. Yingfeng Wang
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Corresponding authors

Correspondence to Wenju Lu or Jian Wang.

Additional information

Y Wang, W Lu, and K Yang contributed equally to this work.

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Wang, Y., Lu, W., Yang, K. et al. Peroxisome proliferator-activated receptor γ inhibits pulmonary hypertension targeting store-operated calcium entry. J Mol Med 93, 327–342 (2015). https://doi.org/10.1007/s00109-014-1216-4

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  • DOI: https://doi.org/10.1007/s00109-014-1216-4

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