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Metabolomic profiling of cellular responses to carvedilol enantiomers in vascular smooth muscle cells.

Wang M, Bai J, Chen WN, Ching CB - PLoS ONE (2010)

Bottom Line: Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood.A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction.Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

View Article: PubMed Central - PubMed

Affiliation: School of Chemical and Biomedical Engineering, College of Engineering, Nanyang Technological University, Singapore, Singapore.

ABSTRACT
Carvedilol is a non-selective β-blocker indicated in the treatment of hypertension and heart failure. Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood. Here we report the use of GC-MS metabolomic profiling to study the effects of Carvedilol enantiomers on vascular smooth muscle cells (A7r5) and to shed new light on molecular events underlying Carvedilol treatment. The metabolic analysis revealed alternations in the levels of 8 intracellular metabolites and 5 secreted metabolites in A7r5 cells incubated separately with S- and R-Carvedilol. Principal component analysis of the metabolite data demonstrated the characteristic metabolic signatures in S- and R-Carvedilol-treated cells. A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction. Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

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Principal component analysis (PCA) of the GC-MS spectra from intracellular metabolites in A7r5 cells.A) PCA scores plot. Solvent control (red), S-Carvedilol (blue) and R-Carvedilol (green) are included. B) PCA loading plot.
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pone-0015441-g002: Principal component analysis (PCA) of the GC-MS spectra from intracellular metabolites in A7r5 cells.A) PCA scores plot. Solvent control (red), S-Carvedilol (blue) and R-Carvedilol (green) are included. B) PCA loading plot.

Mentions: Multivariate statistical modeling using principal component analysis (PCA) was performed on the GC-MS spectra of four independently grown replicates. PCA has been successfully applied to build classification models from metabolomics data [15], [16], [17], [18]. The scores plot (Figure 2a) resulting from PCA revealed clear discrimination between the intracellular metabolome of A7r5 cells incubated with S- and R-Carvedilol, indicating that A7r5 cells displayed distinctly metabolic characteristics under individual Carvedilol enantiomer treatment. It was also found out that L-serine, palmitic acid and myristic acid contributed more significantly to distinguishing A7r5 cells incubated with S- or R-Carvedilol after loadings plot analysis (Figure 2b).


Metabolomic profiling of cellular responses to carvedilol enantiomers in vascular smooth muscle cells.

Wang M, Bai J, Chen WN, Ching CB - PLoS ONE (2010)

Principal component analysis (PCA) of the GC-MS spectra from intracellular metabolites in A7r5 cells.A) PCA scores plot. Solvent control (red), S-Carvedilol (blue) and R-Carvedilol (green) are included. B) PCA loading plot.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2991354&req=5

pone-0015441-g002: Principal component analysis (PCA) of the GC-MS spectra from intracellular metabolites in A7r5 cells.A) PCA scores plot. Solvent control (red), S-Carvedilol (blue) and R-Carvedilol (green) are included. B) PCA loading plot.
Mentions: Multivariate statistical modeling using principal component analysis (PCA) was performed on the GC-MS spectra of four independently grown replicates. PCA has been successfully applied to build classification models from metabolomics data [15], [16], [17], [18]. The scores plot (Figure 2a) resulting from PCA revealed clear discrimination between the intracellular metabolome of A7r5 cells incubated with S- and R-Carvedilol, indicating that A7r5 cells displayed distinctly metabolic characteristics under individual Carvedilol enantiomer treatment. It was also found out that L-serine, palmitic acid and myristic acid contributed more significantly to distinguishing A7r5 cells incubated with S- or R-Carvedilol after loadings plot analysis (Figure 2b).

Bottom Line: Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood.A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction.Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

View Article: PubMed Central - PubMed

Affiliation: School of Chemical and Biomedical Engineering, College of Engineering, Nanyang Technological University, Singapore, Singapore.

ABSTRACT
Carvedilol is a non-selective β-blocker indicated in the treatment of hypertension and heart failure. Although the differential pharmacological effects of individual Carvedilol enantiomer is supported by preceding studies, the cellular response to each enantiomer is not well understood. Here we report the use of GC-MS metabolomic profiling to study the effects of Carvedilol enantiomers on vascular smooth muscle cells (A7r5) and to shed new light on molecular events underlying Carvedilol treatment. The metabolic analysis revealed alternations in the levels of 8 intracellular metabolites and 5 secreted metabolites in A7r5 cells incubated separately with S- and R-Carvedilol. Principal component analysis of the metabolite data demonstrated the characteristic metabolic signatures in S- and R-Carvedilol-treated cells. A panel of metabolites, including L-serine, L-threonine, 5-oxoproline, myristic acid, palmitic acid and inositol are closely correlated to the vascular smooth muscle contraction. Our findings reveal the differentiating metabolites for A7r5 cells incubated with individual enantiomer of Carvedilol, which opens new perspectives to employ metabolic profiling platform to study chiral drug-cell interactions and aid their incorporation into future improvement of β-blocker therapy.

Show MeSH
Related in: MedlinePlus