Abstract
Capacitative Ca(2+) entry (CCE) through store-operated Ca(2+) (SOC) channels plays an important role in returning Ca(2+) to the sarcoplasmic reticulum (SR) and regulating cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)). A rise in [Ca(2+)](cyt) and sufficient Ca(2+) in the SR are required for pulmonary artery smooth muscle cell (PASMC) proliferation. We tested the hypothesis that platelet-derived growth factor (PDGF)-mediated PASMC growth involves upregulation of c-Jun and TRPC6, a transient receptor potential cation channel. In rat PASMC, PDGF (10 ng/ml for 0.5-48 h) phosphorylated signal transducer and activator of transcription (STAT3), increased mRNA and protein levels of c-Jun, and stimulated cell proliferation. PDGF treatment also upregulated TRPC6 expression and augmented CCE, elicited by passive depletion of Ca(2+) from the SR using cyclopiazonic acid. Furthermore, overexpression of c-Jun stimulated TRPC6 expression and CCE amplitude in PASMC. Downregulation of TRPC6 using an antisense oligonucleotide specifically for human TRPC6 decreased CCE and inhibited PDGF-mediated PASMC proliferation. These results suggest that PDGF-mediated PASMC proliferation is associated with c-Jun/STAT3-induced upregulation of TRPC6 expression. The resultant increase in CCE raises [Ca(2+)](cyt), facilitates return of Ca(2+) to the SR, and enhances PASMC growth.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium / metabolism
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Calcium Channel Blockers / pharmacology
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Calcium Channels / drug effects
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Calcium Channels / genetics
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Calcium Channels / metabolism*
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Calcium Signaling / drug effects
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Calcium Signaling / physiology
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Calcium-Transporting ATPases / antagonists & inhibitors
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Calcium-Transporting ATPases / metabolism
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Cell Division / drug effects
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Cell Division / physiology*
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Cells, Cultured
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Culture Media, Serum-Free / pharmacology
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DNA-Binding Proteins / drug effects
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DNA-Binding Proteins / metabolism
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Genetic Vectors
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Lung / blood supply
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Lung / growth & development
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Lung / metabolism*
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Male
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects
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Muscle, Smooth, Vascular / metabolism*
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Platelet-Derived Growth Factor / metabolism*
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Platelet-Derived Growth Factor / pharmacology
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Proto-Oncogene Proteins c-jun / genetics
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Pulmonary Artery / cytology
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Pulmonary Artery / metabolism*
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RNA, Messenger / drug effects
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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STAT3 Transcription Factor
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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TRPC Cation Channels
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Trans-Activators / drug effects
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Trans-Activators / metabolism
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Up-Regulation / drug effects
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Up-Regulation / physiology*
Substances
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Calcium Channel Blockers
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Calcium Channels
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Culture Media, Serum-Free
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DNA-Binding Proteins
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Enzyme Inhibitors
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-jun
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RNA, Messenger
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STAT3 Transcription Factor
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Stat3 protein, rat
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TRPC Cation Channels
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Trans-Activators
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Sarcoplasmic Reticulum Calcium-Transporting ATPases
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Calcium-Transporting ATPases
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Calcium