Increase in caveolae and caveolin-1 expression modulates agonist-induced contraction and store- and receptor-operated Ca(2+) entry in pulmonary arteries of pulmonary hypertensive rats

• Published in: Vascular pharmacology 2016-09, Vol.84, p.55-66
• Main Authors: Jiao, Hai-Xia, Mu, Yun-Ping, Gui, Long-Xin, Yan, Fu-Rong, Lin, Da-Cen, Sham, James S K, Lin, Mo-Jun
• Format: Article
• Language: English
• Subjects: Animals; Calcium - metabolism; Calcium Signaling - drug effects; Caveolae - metabolism; Caveolin 1 - genetics; Caveolin 1 - metabolism; Disease Models, Animal; Gene Expression; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - pathology; Male; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Pulmonary Artery - drug effects; Pulmonary Artery - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - metabolism; Vasoconstriction - drug effects; Vasoconstrictor Agents - pharmacology
• ISSN: 1879-3649
• DOI: 10.1016/j.vph.2016.06.004

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 Ca(2+) entry (SOCE) and receptor-operated Ca(2+) entry (ROCE). However, the contributions of caveolae/Cav-1 of pulmonary arterial smooth muscle cells (PASMCs) to the altered Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.