Biphasic effects of angiotensin II and receptor antagonism on aggregability and protein kinase C phosphorylation in human platelets

Kimiaki Utsugisawa; Hideki Kizawa; Yuriko Nagane; Ryushi Kondoh; Yoko Iwa; Hitomi Akutsu; Hideo Tohgi; Yasuo Terayama

doi:10.1160/TH05-02-0125

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2005; 94(05): 1012-1018
DOI: 10.1160/TH05-02-0125

Platelets and Blood Cells

Schattauer GmbH

Biphasic effects of angiotensin II and receptor antagonism on aggregability and protein kinase C phosphorylation in human platelets

Autoren

Kimiaki Utsugisawa

¹Department of Neurology, Iwate Medical University, Morioka, Japan
Hideki Kizawa

¹Department of Neurology, Iwate Medical University, Morioka, Japan
Yuriko Nagane

¹Department of Neurology, Iwate Medical University, Morioka, Japan
Ryushi Kondoh

¹Department of Neurology, Iwate Medical University, Morioka, Japan
Yoko Iwa

¹Department of Neurology, Iwate Medical University, Morioka, Japan
Hitomi Akutsu

²High-Tech Research Center, Iwate Medical University, Morioka, Japan
Hideo Tohgi

¹Department of Neurology, Iwate Medical University, Morioka, Japan
Yasuo Terayama

¹Department of Neurology, Iwate Medical University, Morioka, Japan

Abstract

Summary

In order to define the role of angiotensin II (AngII) receptor subtypes, AT1 and AT2, in platelet activation, we examined the effects of AngII and receptor antagonists on both aggregability and phosphorylation status of protein kinase C (PKC) isoforms in human platelets obtained from 56 healthy volunteers. AngII promoted both spontaneous and agonist (collagen and ADP) stimulated platelet aggregation at concentrations of 10 nM or less, but the promotion effects were lost at 100 nM. Antagonism of AT1 receptor inhibited the promotion effects of AngII at 10 nM or less. On the other hand, antagonism of AT2 receptor enhanced platelet aggregability modestly with AngII at 10 nM or less, and markedly with 100 nM AngII. Furthermore, with 10 nM AngII, phospho-PKCα/βII expression in platelets was increased after collagen stimulation and was inhibited by antagonism of AT1 receptor. With 100 nM AngII, expression levels of phospho-PKCα/ βII remained low even after collagen stimulation but were markedly enhanced by antagonism of AT2 receptor. These findings suggest that at 10 nM or below, AngII promotes aggregability and PKC phosphorylation in human platelets through the AT1 receptor, which can be inhibited by AT1 receptor antagonists, but at higher concentrations, the promotion effects were lost through the opposing action of the AT2 receptor. The present study may provide an additional mechanism for AT1 receptor antagonism, which would provide clinical benefit to patients with stroke or cardiovascular disease accompanied by hypertension.

Keywords

Angiotensin II - AT1 receptor - platelet aggregation - protein kinase C - sartan

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