Peroxisome proliferator-activated receptor g-mediated inhibition on hypoxia-triggered store-operated calcium entry a caveolin-1-dependent mechanism

Kai Yang, Wenju Lu, Qian Jiang, Xin Yun, Mingming Zhao, Haiyang Jiang, Jian Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Our previous publication demonstrated that peroxisome proliferator-activated receptor g (PPARg) inhibits the pathogenesis of chronic hypoxia (CH)-induced pulmonary hypertension by targeting store-operated calcium entry (SOCE) in rat distal pulmonary arterial smooth muscle cells (PASMCs). In this study, we aim to determine the role of a membrane scaffolding protein, caveolin-1, during the suppressive process ofPPARg on SOCE. Adult (6-8 weeks) male Wistar rats (200-250 g) were exposed to CH (10% O2) for 21 days to establish CH-induced pulmonary hypertension. Primary cultured rat distal PASMCs were applied for the molecular biological experiments. First, hypoxic exposure led to 2.5-fold and 1-fold increases of caveolin-1 protein expression in the distal pulmonary arteries and PASMCs, respectively. Second, effective knockdown of caveolin-1 significantly reduced hypoxia-induced SOCE for 58.2% and 41.5%, measured by Mn21 quenching and extracellular Ca21 restoration experiments, respectively. These results suggested that caveolin-1 acts as a crucial regulator of SOCE, and hypoxia-up-regulated caveolin-1 largely accounts for hypoxia-elevated SOCE in PASMCs. Then, by using a high-potency PPARg agonist, GW1929, we detected that PPARg activation inhibited SOCE and caveolin-1 protein for 62.5% and 59.8% under hypoxia, respectively, suggesting that caveolin-1 also acts as a key target during the suppressive process of PPARg on SOCE in PASMCs. Moreover, by using effective small interfering RNAs against PPARg and caveolin-1, and PPARg antagonist, T0070907, we observed that PPARg plays an inhibitory role on caveolin-1 protein by promoting its lysosomal degradation, without affecting the messenger RNA level. PPARg inhibits SOCE, at least partially, by suppressing cellular caveolin-1 protein in PASMCs.

Original languageEnglish (US)
Pages (from-to)882-892
Number of pages11
JournalAmerican journal of respiratory cell and molecular biology
Volume53
Issue number6
DOIs
StatePublished - Dec 2015

Keywords

  • Caveolin-1
  • Peroxisome proliferator-activated receptor g
  • Pulmonary arterial smooth muscle cells
  • Pulmonary hypertension
  • Store-operated calcium entry

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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