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.
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.
['Jiao|Hai-Xia|HX|', 'Mu|Yun-Ping|YP|', 'Gui|Long-Xin|LX|', 'Yan|Fu-Rong|FR|', 'Lin|Da-Cen|DC|', 'Sham|James S K|JS|', 'Lin|Mo-Jun|MJ|']
D000818:Animals D002118:Calcium D020013:Calcium Signaling D021941:Caveolae D051242:Caveolin 1 D004195:Disease Models, Animal D015870:Gene Expression D006976:Hypertension, Pulmonary D008297:Male D032389:Myocytes, Smooth Muscle D011651:Pulmonary Artery D012333:RNA, Messenger D051381:Rats D017207:Rats, Sprague-Dawley D014661:Vasoconstriction D014662:Vasoconstrictor Agents
Caveolae Caveolin-1 Pulmonary hypertension Chronic hypoxia Monocrotaline Receptor-operated calcium entry Store-operated calcium entry