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.
Highlights
The mortality of cardiovascular diseases including atherosclerosis characterized by vascular inflammation and endothelial damage/dysfunction remains the leading cause of death all overPLOS ONE | DOI:10.1371/journal.pone.0127054 May 13, 2015Nifedipine Inhibits soluble CD40 and its ligand (CD40L) (sCD40L) Release from Human Platelets the world [1,2]
Several inflammatory and prothrombotic mediators including CD40L stored in α-granules are rapidly translocated to the surface of platelets and released into the plasma when platelets are activated by agonists such as collagen or thrombin
CD40L is a critical inducer for cardiovascular diseases by providing a link between the immune system, atherosclerosis and thrombosis [22], and the plasma level of CD40L has been considered an important marker of platelet activation and the prognosis in cardiovascular diseases
Summary
Nifedipine Inhibits sCD40L Release from Human Platelets the world [1,2]. CD40L stimulates platelet activation and stabilizes arterial thrombi through glycoprotein IIb/IIIa ligand-dependent mechanism [8,9]. These results support the important role of CD40L in the pathogenesis of atherosclerosis. CD40L is stored in α-granules; upon activation, CD40L is rapidly released from α-granules and translocated to the surface membrane of platelets. Targeting surface CD40L expression and sCD40L release can be a promising strategy for alleviating atherosclerosis by blocking the linkage between platelet activation, inflammation and thrombosis
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