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(Hypertension. 2003;42:329.)
© 2003 American Heart Association, Inc.

Scientific Contributions

Amlodipine Modulates THP-1 Cell Adhesion to Vascular Endothelium via Inhibition of Protein Kinase C Signal Transduction

Tao Yu; Ikuo Morita; Kentaro Shimokado; Takehisa Iwai; Masayuki Yoshida

From the Departments of Medical Biochemistry (T.Y., M.Y.), Vascular Surgery (T.Y., T.I.), Cellular Physiological Chemistry (I.M.), and Vascular Medicine (K.S., M.Y.), Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Correspondence to Masayuki Yoshida, MD, Department of Medical Biochemistry, Vascular Medicine, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bldg D-256, Bunkyo-ku, Tokyo 113-8519, Japan, E-mail masavasc{at}tmd.ac.jp

Inflammatory responses play an important role in atherosclerosis. To critically assess the effect of dihydropyridines in inflammatory reactions, we conducted a monocyte-endothelial adhesion assay with monocytic THP-1 cells treated with amlodipine under flow conditions in vitro. THP-1 cells were incubated in the presence of amlodipine (10 µmol/L) for 48 hours and then perfused over activated (interleukin-1ß, 10 U/mL, 4 hours) human umbilical vein endothelial cells. The adhesion of THP-1 cells was significantly reduced after amlodipine treatment (P<0.001); however, flow cytometric analysis reveled that the expression levels of integrins in THP-1 cells were not significantly altered. Furthermore, Western blotting analysis of THP-1 cell lysates revealed that translocation of RhoA from the cytosol to the membrane was significantly diminished after amlodipine treatment. In addition, activation of protein kinase C- and -ß, as well as intracellular calcium influx, induced by phorbol 12-myristate 13-acetate, was diminished after amlodipine treatment. Pretreatment of THP-1 cells with calphostin C, a potent inhibitor of protein kinase C, significantly reduced THP-1 adhesion to vascular endothelium, whereas activation of ß₁-integrin was reduced after amlodipine treatment in THP-1 cells, based on the immunoreactivity of an activation-specific antibody for ß₁-integrin. Similar inhibitory effects were observed when we used freshly isolated peripheral blood mononuclear cells. These findings suggest a potential role for amlodipine in monocyte-endothelial interactions by modulation of protein kinase C- and RhoA-dependent mechanisms, which might account for its vascular protective effects.

Key Words: calcium channel blockers • cell adhesion molecules • monocytes • protein kinases • signal transduction

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