Increase in caveolae and caveolin-1 expression modulates agonist-induced contraction and store- and receptor-operated Ca2+ entry in pulmonary arteries of pulmonary hypertensive rats

Hai Xia Jiao, Yun Ping Mu, Long Xin Gui, Fu Rong Yan, Da Cen Lin, James Sham, Mo Jun Lin

Research output: Contribution to journalArticle

Abstract

Caveolin-1 (Cav-1) is a major component protein associated with caveolae in the plasma membrane and has been identified as a regulator of store-operated Ca2+ entry (SOCE) and receptor-operated Ca2+ entry (ROCE). However, the contributions of caveolae/Cav-1 of pulmonary arterial smooth muscle cells (PASMCs) to the altered Ca2+ signaling pathways in pulmonary arteries (PAs) during pulmonary hypertension (PH) have not been fully characterized. The present study quantified caveolae number and Cav-1 expression, and determined the effects of caveolae disruption on ET-1, cyclopiazonic acid (CPA) and 1-Oleoyl-2-acetyl-glycerol (OAG)-induced contraction in PAs and Ca2+ influx in PASMCs of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH rats. We found that the number of caveolae, and the Cav-1 mRNA and protein levels were increased significantly in PASMCs in both PH models. Disruption of caveolae by cholesterol depletion with methyl-β-cyclodextrin (MβCD) significantly inhibited the contractile response to ET-1, CPA and OAG in PAs of control rats. ET-1, SOCE and ROCE-mediated contractile responses were enhanced, and their susceptibility to MβCD suppression was potentiated in the two PH models. MβCD-induced inhibition was reversed by cholesterol repletion. Introduction of Cav-1 scaffolding domain peptide to mimic Cav-1 upregulation caused significant increase in CPA- and OAG-induced Ca2+ entry in PASMCs of control, CH and MCT-treated groups. Our results suggest that the increase in caveolae and Cav-1 expression in PH contributes to the enhanced agonist-induced contraction of PA via modulation of SOCE and ROCE; and targeting caveolae/Cav-1 in PASMCs may provide a novel therapeutic strategy for the treatment of PH.

Original languageEnglish (US)
JournalVascular Pharmacology
DOIs
StateAccepted/In press - Jan 29 2016

Keywords

  • Caveolae
  • Caveolin-1
  • Chronic hypoxia
  • Monocrotaline
  • Pulmonary hypertension
  • Receptor-operated calcium entry
  • Store-operated calcium entry

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Physiology

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