Document Detail

Regulation of intracellular Ca2+ and calcineurin by NO/PKG in proliferation of vascular smooth muscle cells.
MedLine Citation:
PMID:  15715928     Owner:  NLM     Status:  MEDLINE    
AIM: To determine whether Ca2+/calcineurin mediated the inhibitory effects of nitric oxide /cGMP-dependent protein kinase (NO/PKG) on the proliferation of vascular smooth muscle cells (VSMC).
METHODS: Proliferation and viability of primary VSMC from rat aorta were measured using [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) assay and acridine orange and ethidium bromide staining, respectively. Cytosolic Ca2+ was determined by Fluo-3/AM. Calcineurin protein and its activity were assayed using immunoblotting and free inorganic phosphate analysis, respectively.
RESULTS: (+/-)-S-nitroso-N-acetyl-penicillamine (SNAP) and Sp-8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (Sp-8-pCPT-cGMPS) decreased phenylephrine (PE)-induced proliferation of VSMC by 27.3% and 36.6%, respectively, but Rp-8-[(4-chlorophenyl)thio]-guanosine-3',5'-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS) increased PE-induced proliferation of VSMC. SNAP, Sp-8-pCPT-cGMPS, and Rp-8-pCPT-cGMPS did not affect the viability of VSMC. Calcineurin protein was decreased by 63.1% and its activity was decreased by 59.7% in smooth muscle cells (SMC) pretreated with verapamil (Ver) and then stimulated by PE. In SMC pretreated with Ver, the absorbance of cells stimulated by PE decreased by 22.0% and was further inhibited by the additional treatment of SNAP and Sp-8-pCPT-cGMPS. In SMC pretreated with cyclosporin A (CsA), the absorbance of cells stimulated by PE decreased by 36.7%, but could not be further altered by the additional treatment of SNAP, Sp-8-pCPT-cGMPS, and Rp-8-pCPT-cGMPS. In addition, Ver inhibited PE-induced intracellular Ca2+ variations, which could be further inhibited by SNAP and Sp-8-pCPT-cGMPS, but not by Rp-8-pCPT-cGMPS. Moreover, the increase in calcineurin activity induced by PE was inhibited by SNAP and Sp-8-pCPT-cGMPS, but was promoted by Rp-8-pCPT-cGMPS.
CONCLUSION: NO/PKG regulates calcineurin activity via the modulation of intracellular Ca2+ concentration, and thus partially inhibits the proliferation of VSMC without affecting their viability.
Shi-jun Li; Ning-ling Sun
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  26     ISSN:  1671-4083     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-02-17     Completed Date:  2005-10-25     Revised Date:  2014-07-29    
Medline Journal Info:
Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  China    
Other Details:
Languages:  eng     Pagination:  323-8     Citation Subset:  IM    
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MeSH Terms
Animals, Newborn
Aorta, Thoracic
Calcineurin / metabolism*
Calcium / metabolism*
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Cyclic GMP / analogs & derivatives*,  pharmacology
Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
Muscle, Smooth, Vascular / cytology,  metabolism*
Nitric Oxide Donors / pharmacology
Penicillamine / analogs & derivatives*,  pharmacology
Phenylephrine / pharmacology
Rats, Wistar
Thionucleotides / pharmacology*
Verapamil / pharmacology
Reg. No./Substance:
0/8-(4-chlorophenylthio)guanosine 3',5'-cyclic monophosphorothioate; 0/Nitric Oxide Donors; 0/S-nitro-N-acetylpenicillamine; 0/Thionucleotides; 1WS297W6MV/Phenylephrine; CJ0O37KU29/Verapamil; EC GMP-Dependent Protein Kinases; EC; GNN1DV99GX/Penicillamine; H2D2X058MU/Cyclic GMP; SY7Q814VUP/Calcium

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