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Mechanisms of Nifedipine-Downregulated CD40L/sCD40L Signaling in Collagen Stimulated Human Platelets.

Chen TH, Shih CY, Hsu WL, Chou TC - PLoS ONE (2015)

Bottom Line: Nifedipine, a dihydropyridine-based L-type calcium channel blocker (CCB), has been reported to have an anti-atherosclerotic effect beyond its blood pressure-lowering effect, but the molecular mechanisms remain unclear.When the NO/cyclic GMP pathway was suppressed, nifedipine-mediated inhibition of sCD40L release was abolished significantly.Collagen-induced phosphorylation of p38MAPK, ERK1/2 and HSP27, matrix metalloproteinase-2 (MMP-2) expression/activity and reactive oxygen species (ROS) formation were significantly inhibited by nifedipine, whereas these alterations were all attenuated by co-treatment with PPAR-β/-γ antagonists.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

ABSTRACT
The platelet-derived soluble CD40L (sCD40L) release plays a critical role in the development of atherosclerosis. Nifedipine, a dihydropyridine-based L-type calcium channel blocker (CCB), has been reported to have an anti-atherosclerotic effect beyond its blood pressure-lowering effect, but the molecular mechanisms remain unclear. The present study was designed to investigate whether nifedipine affects sCD40L release from collagen-stimulated human platelets and to determine the potential role of peroxisome proliferator-activated receptor-β/-γ (PPAR-β/-γ). We found that treatment with nifedipine significantly inhibited the platelet surface CD40L expression and sCD40L release in response to collagen, while the inhibition was markedly reversed by blocking PPAR-β/-γ activity with specific antagonist such as GSK0660 and GW9662. Meanwhile, nifedipine also enhanced nitric oxide (NO) and cyclic GMP formation in a PPAR-β/-γ-dependent manner. When the NO/cyclic GMP pathway was suppressed, nifedipine-mediated inhibition of sCD40L release was abolished significantly. Collagen-induced phosphorylation of p38MAPK, ERK1/2 and HSP27, matrix metalloproteinase-2 (MMP-2) expression/activity and reactive oxygen species (ROS) formation were significantly inhibited by nifedipine, whereas these alterations were all attenuated by co-treatment with PPAR-β/-γ antagonists. Collectively, these results demonstrate that PPAR-β/-γ-dependent pathways contribute to nifedipine-mediated downregulation of CD40L/sCD40L signaling in activated platelets through regulation of NO/ p38MAPK/ERK1/2/HSP27/MMP-2 signalings and provide a novel mechanism regarding the anti-atherosclerotic effect of nifedipine.

No MeSH data available.


Related in: MedlinePlus

Effects of PPAR-β/-γ antagonists on nifedipine-mediated MMP2 activity.Platelets were treated with nifedipine (5 μ M), or nifedipine combined with various drugs for 3 min, followed by addition of collagen for 6 min. The MMP-2 expression (A) and MMP-2 activity (B) were determined. Date were expressed as means ± SEM (n = 5). ***p < 0.001 compared with collagen alone group; ++p < 0.01, +++p < 0.001 compared with respective collagen+nifedipine-treated group.
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pone.0127054.g004: Effects of PPAR-β/-γ antagonists on nifedipine-mediated MMP2 activity.Platelets were treated with nifedipine (5 μ M), or nifedipine combined with various drugs for 3 min, followed by addition of collagen for 6 min. The MMP-2 expression (A) and MMP-2 activity (B) were determined. Date were expressed as means ± SEM (n = 5). ***p < 0.001 compared with collagen alone group; ++p < 0.01, +++p < 0.001 compared with respective collagen+nifedipine-treated group.

Mentions: MMP-2 is a critical step for cleaving the membrane-bound CD40L leading to release of sCD40L [10]. Our data showed that collagen-induced rise of MMP-2 expression (Fig 4A) and activity (Fig 4B) were markedly inhibited by nifedipine, but the effects were completely diminished when platelets were co-treated with PPAR-β/-γ antagonists.


Mechanisms of Nifedipine-Downregulated CD40L/sCD40L Signaling in Collagen Stimulated Human Platelets.

Chen TH, Shih CY, Hsu WL, Chou TC - PLoS ONE (2015)

Effects of PPAR-β/-γ antagonists on nifedipine-mediated MMP2 activity.Platelets were treated with nifedipine (5 μ M), or nifedipine combined with various drugs for 3 min, followed by addition of collagen for 6 min. The MMP-2 expression (A) and MMP-2 activity (B) were determined. Date were expressed as means ± SEM (n = 5). ***p < 0.001 compared with collagen alone group; ++p < 0.01, +++p < 0.001 compared with respective collagen+nifedipine-treated group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4430314&req=5

pone.0127054.g004: Effects of PPAR-β/-γ antagonists on nifedipine-mediated MMP2 activity.Platelets were treated with nifedipine (5 μ M), or nifedipine combined with various drugs for 3 min, followed by addition of collagen for 6 min. The MMP-2 expression (A) and MMP-2 activity (B) were determined. Date were expressed as means ± SEM (n = 5). ***p < 0.001 compared with collagen alone group; ++p < 0.01, +++p < 0.001 compared with respective collagen+nifedipine-treated group.
Mentions: MMP-2 is a critical step for cleaving the membrane-bound CD40L leading to release of sCD40L [10]. Our data showed that collagen-induced rise of MMP-2 expression (Fig 4A) and activity (Fig 4B) were markedly inhibited by nifedipine, but the effects were completely diminished when platelets were co-treated with PPAR-β/-γ antagonists.

Bottom Line: Nifedipine, a dihydropyridine-based L-type calcium channel blocker (CCB), has been reported to have an anti-atherosclerotic effect beyond its blood pressure-lowering effect, but the molecular mechanisms remain unclear.When the NO/cyclic GMP pathway was suppressed, nifedipine-mediated inhibition of sCD40L release was abolished significantly.Collagen-induced phosphorylation of p38MAPK, ERK1/2 and HSP27, matrix metalloproteinase-2 (MMP-2) expression/activity and reactive oxygen species (ROS) formation were significantly inhibited by nifedipine, whereas these alterations were all attenuated by co-treatment with PPAR-β/-γ antagonists.

View Article: PubMed Central - PubMed

Affiliation: Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.

ABSTRACT
The platelet-derived soluble CD40L (sCD40L) release plays a critical role in the development of atherosclerosis. Nifedipine, a dihydropyridine-based L-type calcium channel blocker (CCB), has been reported to have an anti-atherosclerotic effect beyond its blood pressure-lowering effect, but the molecular mechanisms remain unclear. The present study was designed to investigate whether nifedipine affects sCD40L release from collagen-stimulated human platelets and to determine the potential role of peroxisome proliferator-activated receptor-β/-γ (PPAR-β/-γ). We found that treatment with nifedipine significantly inhibited the platelet surface CD40L expression and sCD40L release in response to collagen, while the inhibition was markedly reversed by blocking PPAR-β/-γ activity with specific antagonist such as GSK0660 and GW9662. Meanwhile, nifedipine also enhanced nitric oxide (NO) and cyclic GMP formation in a PPAR-β/-γ-dependent manner. When the NO/cyclic GMP pathway was suppressed, nifedipine-mediated inhibition of sCD40L release was abolished significantly. Collagen-induced phosphorylation of p38MAPK, ERK1/2 and HSP27, matrix metalloproteinase-2 (MMP-2) expression/activity and reactive oxygen species (ROS) formation were significantly inhibited by nifedipine, whereas these alterations were all attenuated by co-treatment with PPAR-β/-γ antagonists. Collectively, these results demonstrate that PPAR-β/-γ-dependent pathways contribute to nifedipine-mediated downregulation of CD40L/sCD40L signaling in activated platelets through regulation of NO/ p38MAPK/ERK1/2/HSP27/MMP-2 signalings and provide a novel mechanism regarding the anti-atherosclerotic effect of nifedipine.

No MeSH data available.


Related in: MedlinePlus