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ORIGINAL ARTICLE

Effect of Azelnidipine on Angiotensin II-Mediated Growth-Promoting Signaling in Vascular Smooth Muscle Cells

Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Ehime, Japan

Abstract

The detailed mechanism of the effects of extracellular Ca²⁺ entry blockade on angiotensin II (Ang II) type 1 (AT1) receptor-mediated growth-promoting signals in vascular smooth muscle cells (VSMCs) is not fully understood. Ang II stimulation caused biphasic activation of growth-promoting signals, reaching a peak at 5 to 10 min followed by a decrease and a second peak at around 2 to 4 h. Addition of PD98059 (2'-amino-3'-methoxyflavone), a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor, or AG490 [-cyano-(3,4-dihydroxy)-N-benzylcinnamide], a Janus-activated kinase 2 (Jak2) inhibitor, even 4 h after Ang II treatment inhibited [³H]thymidine incorporation. The calcium channel blocker azelnidipine attenuated the later peaks of extracellular signal-regulated kinase (ERK), tyrosine kinase 2, Jak2 activation, and phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3. Interestingly, azelnidipine increased rather than decreased the later ERK peaks in cells treated with small interfering RNA against mitogen-activated protein kinase phosphatase-1. Ang II-mediated [³H]thymidine incorporation was inhibited dose dependently by azelnidipine and also by azelnidipine, plus olmesartan, whereas olmesartan or azelnidipine alone at such lower doses did not affect [³H]thymidine incorporation. These data provide new insight into the manner in which calcium channels exert an essential action in the AT1 receptor-mediated growth-promoting actions in VSMCs.

Address correspondence to: Dr. Masatsugu Horiuchi, Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Tohon, Ehime 791-0295, Japan. E-mail: horiuchi{at}m.ehime-u.ac.jp

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