SDF-1-induced adhesion of monocytes to vascular endothelium is modulated by azelnidipine via protein kinase C inhibition.

Abstract

Monocyte-endothelial interaction and its modulation by chemokines play a key role in atherogenesis and inflammation. We examined the potential effects of stromal cell-derived factor (SDF-1) and azelnidipine, a novel dihydropyridine derivative, toward monocyte-endothelial interaction. Human monocytes were prepared from peripheral blood mononuclear cells obtained from healthy volunteers and pretreated with azelnidipine (1 microM) for 48 h, after which their adhesion to interleukin-1beta (IL-1beta)-activated human umbilical vein endothelial cells (HUVECs) was analyzed using an in vitro flow apparatus with a shear stress of 1 dyn/cm(2). In some experiments, monocytes were incubated in the presence of stromal cell-derived factor (SDF-1), a chemokine, just prior to the assay. Pre-incubation of monocytes with SDF-1 enhanced their adhesion to activated HUVECs. When monocytes were pre-incubated in the presence of azelnidipine, baseline levels as well as SDF-1-induced monocyte adhesion levels were reduced. Interestingly, the surface expressions of the adhesion molecules CD11a, CD11b, and CD36, were not changed by azelnidipine treatment. Western blotting analysis revealed that activation of protein kinase C (PKC)alpha was inhibited by azelnidipine treatment, while it also reduced the SDF-1-induced increase in intracellular calcium concentration ([Ca(2+)](i)). Further, pre-incubation of monocytes with Go6976, a potent inhibitor of PKCalpha, significantly reduced monocyte adhesion to HUVECs. Our results demonstrated an inhibitory action of azelnidipine toward adhesive interactions of monocytes to HUVECs, which involves inhibition of PKCalpha and a reduction in [Ca(2+)](i). These findings imply a protective role of azelnidipine against inflammation in atherosclerosis.

• Authors: Keiko Takahashi, Kentaro Shimokado, Masayuki Yoshida
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 552 Issue 1-3 Pg. 162-9 (Dec 15 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 17067573 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CXCL12 protein, human
• Calcium Channel Blockers
• Carbazoles
• Cell Adhesion Molecules
• Chemokine CXCL12
• Chemokines, CXC
• Dihydropyridines
• Enzyme Inhibitors
• Indoles
• Interleukin-1beta
• Ionophores
• Go 6976
• Azetidinecarboxylic Acid
• Protein Kinase C-alpha
• Mitogen-Activated Protein Kinases
• azelnidipine
• Calcium

Topics

• Azetidinecarboxylic Acid (analogs & derivatives, pharmacology)
• Blotting, Western
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Carbazoles (pharmacology)
• Cell Adhesion (drug effects)
• Cell Adhesion Molecules (metabolism)
• Cell Line
• Cells, Cultured
• Chemokine CXCL12
• Chemokines, CXC (pharmacology)
• Dihydropyridines (pharmacology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (cytology, drug effects, metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Flow Cytometry
• Humans
• Indoles (pharmacology)
• Interleukin-1beta (pharmacology)
• Ionophores (pharmacology)
• Mitogen-Activated Protein Kinases (metabolism)
• Monocytes (cytology, drug effects, metabolism)
• Protein Kinase C-alpha (antagonists & inhibitors, metabolism)