Sodium tanshinone IIA sulfonate inhibits hypoxia-induced enhancement of SOCE in pulmonary arterial smooth muscle cells via the PKG-PPAR-γ signaling axis

Qian Jiang, Wenju Lu, Kai Yang, Cyrus Hadadi, Xin Fu, Yuqin Chen, Xin Yun, Jie Zhang, Meichan Li, Lei Xu, Haiyang Tang, Jason Yuan, Jian Wang, Dejun Sun

Research output: Contribution to journalArticle

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Abstract

Our laboratory previously showed that sodium tanshinone IIA sulfonate (STS) inhibited storeoperated Ca2+ entry (SOCE) through store-operated Ca2+ channels (SOCC) via downregulating the expression of transient receptor potential canonical proteins (TRPC), which contribute to the formation of SOCC (Wang J, Jiang Q, Wan L, Yang K, Zhang Y, Chen Y, Wang E, Lai N, Zhao L, Jiang H, Sun Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 48: 125–134, 2013). The detailed molecular mechanisms by which STS inhibits SOCE and downregulates TRPC, however, remain largely unknown. We have previously shown that, under hypoxic conditions, inhibition of protein kinase G (PKG) and peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling axis results in the upregulation of TRPC (Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 49: 231–240, 2013). This suggests that strategies targeting the restoration of this signaling pathway may be an effective treatment strategy for pulmonary hypertension. In this study, our results demonstrated that STS treatment can effectively prevent the hypoxiamediated inhibition of the PKG-PPAR-γ signaling axis in rat distal pulmonary arterial smooth muscle cells (PASMCs) and distal pulmonary arteries. These effects of STS treatment were blocked by pharmacological inhibition or specific small interfering RNA knockdown of either PKG or PPAR-γ. Moreover, targeted PPAR-γ agonist markedly enhanced the beneficial effects of STS. These results comprehensively suggest that STS treatment can prevent hypoxia-mediated increases in intracellular calcium homeostasis and cell proliferation, by targeting and restoring the hypoxia-inhibited PKG-PPAR-γ signaling pathway in PASMCs.

Original languageEnglish (US)
Pages (from-to)C136-C149
JournalAmerican Journal of Physiology - Cell Physiology
Volume311
Issue number1
DOIs
StatePublished - Jul 1 2016

Fingerprint

Cyclic GMP-Dependent Protein Kinases
Peroxisome Proliferator-Activated Receptors
Smooth Muscle Myocytes
Lung
Yang Deficiency
Down-Regulation
Proteins
Solar System
Pulmonary Hypertension
Small Interfering RNA
Pulmonary Artery
Hypoxia
tanshinone II A sodium sulfonate
Homeostasis
Up-Regulation
Cell Proliferation
Pharmacology
Calcium

Keywords

  • PKG
  • PPAR-γ
  • SOCE
  • STS
  • TRPC

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

Sodium tanshinone IIA sulfonate inhibits hypoxia-induced enhancement of SOCE in pulmonary arterial smooth muscle cells via the PKG-PPAR-γ signaling axis. / Jiang, Qian; Lu, Wenju; Yang, Kai; Hadadi, Cyrus; Fu, Xin; Chen, Yuqin; Yun, Xin; Zhang, Jie; Li, Meichan; Xu, Lei; Tang, Haiyang; Yuan, Jason; Wang, Jian; Sun, Dejun.

In: American Journal of Physiology - Cell Physiology, Vol. 311, No. 1, 01.07.2016, p. C136-C149.

Research output: Contribution to journalArticle

Jiang, Qian ; Lu, Wenju ; Yang, Kai ; Hadadi, Cyrus ; Fu, Xin ; Chen, Yuqin ; Yun, Xin ; Zhang, Jie ; Li, Meichan ; Xu, Lei ; Tang, Haiyang ; Yuan, Jason ; Wang, Jian ; Sun, Dejun. / Sodium tanshinone IIA sulfonate inhibits hypoxia-induced enhancement of SOCE in pulmonary arterial smooth muscle cells via the PKG-PPAR-γ signaling axis. In: American Journal of Physiology - Cell Physiology. 2016 ; Vol. 311, No. 1. pp. C136-C149.
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AU - Jiang, Qian

AU - Lu, Wenju

AU - Yang, Kai

AU - Hadadi, Cyrus

AU - Fu, Xin

AU - Chen, Yuqin

AU - Yun, Xin

AU - Zhang, Jie

AU - Li, Meichan

AU - Xu, Lei

AU - Tang, Haiyang

AU - Yuan, Jason

AU - Wang, Jian

AU - Sun, Dejun

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AB - Our laboratory previously showed that sodium tanshinone IIA sulfonate (STS) inhibited storeoperated Ca2+ entry (SOCE) through store-operated Ca2+ channels (SOCC) via downregulating the expression of transient receptor potential canonical proteins (TRPC), which contribute to the formation of SOCC (Wang J, Jiang Q, Wan L, Yang K, Zhang Y, Chen Y, Wang E, Lai N, Zhao L, Jiang H, Sun Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 48: 125–134, 2013). The detailed molecular mechanisms by which STS inhibits SOCE and downregulates TRPC, however, remain largely unknown. We have previously shown that, under hypoxic conditions, inhibition of protein kinase G (PKG) and peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling axis results in the upregulation of TRPC (Wang J, Yang K, Xu L, Zhang Y, Lai N, Jiang H, Zhang Y, Zhong N, Ran P, Lu W. Am J Respir Cell Mol Biol 49: 231–240, 2013). This suggests that strategies targeting the restoration of this signaling pathway may be an effective treatment strategy for pulmonary hypertension. In this study, our results demonstrated that STS treatment can effectively prevent the hypoxiamediated inhibition of the PKG-PPAR-γ signaling axis in rat distal pulmonary arterial smooth muscle cells (PASMCs) and distal pulmonary arteries. These effects of STS treatment were blocked by pharmacological inhibition or specific small interfering RNA knockdown of either PKG or PPAR-γ. Moreover, targeted PPAR-γ agonist markedly enhanced the beneficial effects of STS. These results comprehensively suggest that STS treatment can prevent hypoxia-mediated increases in intracellular calcium homeostasis and cell proliferation, by targeting and restoring the hypoxia-inhibited PKG-PPAR-γ signaling pathway in PASMCs.

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