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Article: Chronic hypoxia-induced upregulation of store-operated and receptor-operated Ca2+ channels in pulmonary arterial smooth muscle cells: A novel mechanism of hypoxic pulmonary hypertension

TitleChronic hypoxia-induced upregulation of store-operated and receptor-operated Ca2+ channels in pulmonary arterial smooth muscle cells: A novel mechanism of hypoxic pulmonary hypertension
Authors
KeywordsPulmonary hypertension
Receptor-operated Ca2+ channels
Store-operated Ca2+ channels
Transient receptor potential channels
Issue Date2004
PublisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.org
Citation
Circulation Research, 2004, v. 95 n. 5, p. 496-505 How to Cite?
AbstractChronic hypoxic pulmonary hypertension is associated with profound vascular remodeling and alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Recent studies show that transient receptor potential (TRPC) genes, which encode store-operated and receptor-operated cation channels, play important roles in Ca2+ regulation and cell proliferation. However, the influence of chronic hypoxia on TRPC channels has not been determined. Here we compared TRPC expression, and store- and receptor-operated Ca2+ entries in PASMCs of normoxic and chronic hypoxic rats. Reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining showed consistently that TRPC1, TRPC3, and TRPC6 were expressed in intralobar pulmonary arteries (PAs) and PASMCs. Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG) to directly activate receptor-operated channels, or thapsigargin to deplete Ca2+ stores, caused dramatic increase in cation entry measured by Mn2+ quenching of fura-2 and by Ca2+ transients. OAG-induced responses were ≈700-fold more resistant to La3+ inhibition than thapsigargin-induced responses. siRNA knockdown of TRPC1 and TRPC6 specifically attenuated thapsigargin- and OAG-induced cation entries, respectively, indicating that TRPC1 mediates store-operated entry and TRPC6 mediates receptor-operated entry. In hypoxic PAs, there were 2- to 3-fold increases in TRPC1 and TRPC6 expression. They were accompanied by significant increases in basal, OAG-induced, and thapsigargin-induced cation entries in hypoxic PASMCs. Moreover, removal of Ca2+ or inhibition of store-operated Ca2+ entry with La3+ and SK&F-96365 reversed the elevated basal [Ca 2+]i in PASMCs and vascular tone in PAs of chronic hypoxic animals, but nifedipine had minimal effects. Our results for the first time to our knowledge show that both store- and receptor-operated channels of PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone in hypoxic pulmonary hypertension.
Persistent Identifierhttp://hdl.handle.net/10722/80288
ISSN
2015 Impact Factor: 11.551
2015 SCImago Journal Rankings: 5.755
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLin, MJen_HK
dc.contributor.authorLeung, GPHen_HK
dc.contributor.authorZhang, WMen_HK
dc.contributor.authorYang, XRen_HK
dc.contributor.authorYip, KPen_HK
dc.contributor.authorTse, CMen_HK
dc.contributor.authorSham, JSKen_HK
dc.date.accessioned2010-09-06T08:04:38Z-
dc.date.available2010-09-06T08:04:38Z-
dc.date.issued2004en_HK
dc.identifier.citationCirculation Research, 2004, v. 95 n. 5, p. 496-505en_HK
dc.identifier.issn0009-7330en_HK
dc.identifier.urihttp://hdl.handle.net/10722/80288-
dc.description.abstractChronic hypoxic pulmonary hypertension is associated with profound vascular remodeling and alterations in Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Recent studies show that transient receptor potential (TRPC) genes, which encode store-operated and receptor-operated cation channels, play important roles in Ca2+ regulation and cell proliferation. However, the influence of chronic hypoxia on TRPC channels has not been determined. Here we compared TRPC expression, and store- and receptor-operated Ca2+ entries in PASMCs of normoxic and chronic hypoxic rats. Reverse-transcription polymerase chain reaction (RT-PCR), Western blot, and immunostaining showed consistently that TRPC1, TRPC3, and TRPC6 were expressed in intralobar pulmonary arteries (PAs) and PASMCs. Application of 1-oleoyl-2-acetyl-sn-glycerol (OAG) to directly activate receptor-operated channels, or thapsigargin to deplete Ca2+ stores, caused dramatic increase in cation entry measured by Mn2+ quenching of fura-2 and by Ca2+ transients. OAG-induced responses were ≈700-fold more resistant to La3+ inhibition than thapsigargin-induced responses. siRNA knockdown of TRPC1 and TRPC6 specifically attenuated thapsigargin- and OAG-induced cation entries, respectively, indicating that TRPC1 mediates store-operated entry and TRPC6 mediates receptor-operated entry. In hypoxic PAs, there were 2- to 3-fold increases in TRPC1 and TRPC6 expression. They were accompanied by significant increases in basal, OAG-induced, and thapsigargin-induced cation entries in hypoxic PASMCs. Moreover, removal of Ca2+ or inhibition of store-operated Ca2+ entry with La3+ and SK&F-96365 reversed the elevated basal [Ca 2+]i in PASMCs and vascular tone in PAs of chronic hypoxic animals, but nifedipine had minimal effects. Our results for the first time to our knowledge show that both store- and receptor-operated channels of PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone in hypoxic pulmonary hypertension.en_HK
dc.languageengen_HK
dc.publisherLippincott Williams & Wilkins. The Journal's web site is located at http://circres.ahajournals.orgen_HK
dc.relation.ispartofCirculation Researchen_HK
dc.rightsCirculation Research. Copyright © Lippincott Williams & Wilkins.en_HK
dc.subjectPulmonary hypertensionen_HK
dc.subjectReceptor-operated Ca2+ channelsen_HK
dc.subjectStore-operated Ca2+ channelsen_HK
dc.subjectTransient receptor potential channelsen_HK
dc.titleChronic hypoxia-induced upregulation of store-operated and receptor-operated Ca2+ channels in pulmonary arterial smooth muscle cells: A novel mechanism of hypoxic pulmonary hypertensionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0009-7330&volume=2004;95&spage=496&epage=505&date=2004&atitle=Chronic+Hypoxia-induced+Upregulation+Of+Store-operated+And+Receptor-operated+Ca2++Channels+In+Pulmonary+Arterial+Smooth+Muscle+Cellsen_HK
dc.identifier.emailLeung, GPH: gphleung@hkucc.hku.hken_HK
dc.identifier.authorityLeung, GPH=rp00234en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1161/01.RES.0000138952.16382.aden_HK
dc.identifier.pmid15256480en_HK
dc.identifier.scopuseid_2-s2.0-4444352981en_HK
dc.identifier.hkuros103488en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-4444352981&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume95en_HK
dc.identifier.issue5en_HK
dc.identifier.spage496en_HK
dc.identifier.epage505en_HK
dc.identifier.isiWOS:000223664100008-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridLin, MJ=37042017600en_HK
dc.identifier.scopusauthoridLeung, GPH=35963668200en_HK
dc.identifier.scopusauthoridZhang, WM=16235070800en_HK
dc.identifier.scopusauthoridYang, XR=8504673700en_HK
dc.identifier.scopusauthoridYip, KP=7101909682en_HK
dc.identifier.scopusauthoridTse, CM=7103295076en_HK
dc.identifier.scopusauthoridSham, JSK=21738467300en_HK

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