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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

Hypothetical model of the signaling pathways of nifedipine-mediated reduction of sCD40L release from collagen-stimulated platelets.Nifedipine initially activates PPAR-β/-γ followed by increased formation of NO/cyclic GMP and down-regulation of p38MAPK/ERK1/2/HSP27 signaling as well as ROS generation, which then attenuates MMP-2 activity and ultimately inhibits sCD40L release from activated platelets.
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pone.0127054.g006: Hypothetical model of the signaling pathways of nifedipine-mediated reduction of sCD40L release from collagen-stimulated platelets.Nifedipine initially activates PPAR-β/-γ followed by increased formation of NO/cyclic GMP and down-regulation of p38MAPK/ERK1/2/HSP27 signaling as well as ROS generation, which then attenuates MMP-2 activity and ultimately inhibits sCD40L release from activated platelets.

Mentions: In conclusion, as summarized in Fig 6, this study provides the first mechanistic evidence that nifedipine-mediated inhibition of the surface CD40L expression and sCD40L release in activated human platelets is modulated by PPAR-β/-γ. Furthermore, we demonstrated that PPAR-β/-γ -dependent elevation of NO/cyclic GMP formation and downregulation of p38MAPK/ERK1/2/HSP27/MMP-2 signaling pathway and ROS production are key events contributing to suppressing sCD40L release in response to nifedipine. The decreased sCD40L release from platelets is likely to contribute to the protective effect of nifedipine on cardiovascular diseases.


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

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

Hypothetical model of the signaling pathways of nifedipine-mediated reduction of sCD40L release from collagen-stimulated platelets.Nifedipine initially activates PPAR-β/-γ followed by increased formation of NO/cyclic GMP and down-regulation of p38MAPK/ERK1/2/HSP27 signaling as well as ROS generation, which then attenuates MMP-2 activity and ultimately inhibits sCD40L release from activated platelets.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0127054.g006: Hypothetical model of the signaling pathways of nifedipine-mediated reduction of sCD40L release from collagen-stimulated platelets.Nifedipine initially activates PPAR-β/-γ followed by increased formation of NO/cyclic GMP and down-regulation of p38MAPK/ERK1/2/HSP27 signaling as well as ROS generation, which then attenuates MMP-2 activity and ultimately inhibits sCD40L release from activated platelets.
Mentions: In conclusion, as summarized in Fig 6, this study provides the first mechanistic evidence that nifedipine-mediated inhibition of the surface CD40L expression and sCD40L release in activated human platelets is modulated by PPAR-β/-γ. Furthermore, we demonstrated that PPAR-β/-γ -dependent elevation of NO/cyclic GMP formation and downregulation of p38MAPK/ERK1/2/HSP27/MMP-2 signaling pathway and ROS production are key events contributing to suppressing sCD40L release in response to nifedipine. The decreased sCD40L release from platelets is likely to contribute to the protective effect of nifedipine on cardiovascular diseases.

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