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 S.K. Sham, Mo Jun Lin

Research output: Contribution to journalArticlepeer-review

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)
Pages (from-to)55-66
Number of pages12
JournalVascular Pharmacology
Volume84
DOIs
StatePublished - Sep 1 2016

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Medicine
  • Pharmacology

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