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.
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; Laboratory of Cardiovascular Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
Hai-Xia
HX
Jiao
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; Laboratory of Cardiovascular Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
Yun-Ping
YP
Mu
Laboratory of Cardiovascular Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
Long-Xin
LX
Gui
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; Laboratory of Cardiovascular Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
Fu-Rong
FR
Yan
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; Laboratory of Cardiovascular Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China.
Da-Cen
DC
Lin
Laboratory of Cardiovascular Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: jsks@jhmi.edu.
James S K
JS
Sham
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China; Laboratory of Cardiovascular Sciences, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, People's Republic of China. Electronic address: mjlin@mail.fjmu.edu.cn.
Mo-Jun
MJ
Lin
D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D021941:Caveolae / Q000378:metabolism*; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D051242:Caveolin 1; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D002118:Calcium
Caveolae; Caveolin-1; Chronic hypoxia; Monocrotaline; Pulmonary hypertension; Receptor-operated calcium entry; Store-operated calcium entry