Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 7, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn064
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Vasoconstrictor effect of aldosterone via angiotensin II type 1 (AT1) receptor: Possible role of AT1 receptor dimerization
From: Department of Cardiology, Hirosaki University Graduate School of Medicine
Correspondence to: Ken Okumura, M.D. Department of Cardiology Hirosaki University Graduate School of Medicine 5 Zaifu-Cho, Hirosaki, 036-8562 Japan Tel: 81-172-39-5057 Fax: 81-172-35-9190 e-mail: okumura{at}cc.hirosaki-u.ac.jp
Aims: We recently demonstrated that aldosterone induces a nongenomic vasoconstrictor effect on rat coronary arterioles and that this effect was blocked by angiotensin II type 1 receptor (AT1) blockers. Intracellular transglutaminase enhances AT1 signaling by crosslinking AT1 homodimers. The purpose of this study was to confirm the AT1-dependency of the vasoconstrictor effect of aldosterone using AT1a knockout (AT1aKO) mice and to investigate the role of intracellular transglutaminase and AT1 dimerization in this effect.
Methods and Results: The mesenteric arterioles (60-160 µm) were isolated from C57BL/6J (wild-type, WT) and AT1aKO mice, and the internal diameter was measured by video microscopy. Aldosterone (10–13 to 10–6 M), but not hydrocortisone, produced a dose-dependent vasoconstriction in WT mice; the maximal diameter change was -8.6±0.3% from the baseline (p<0.001). This vasoconstrictor effect was unaffected by the mineralocorticoid receptor (MR) antagonist spironolactone or eplerenone, the AT2 antagonist PD123319, the glucocorticoid receptor antagonist RU486, or endothelium denudation. Aldosterone's vasoconstrictor effect was negligible in AT1aKO mice. The AT1 blockers valsartan or candesartan suppressed aldosterone-induced vasoconstriction in WT mice. The transglutaminase inhibitors cystamine and monodansyl cadaverine both also suppressed aldosterone's vasoconstrictor effect, without affecting the vasoconstrictor effect of angiotensin II in WT mice. AT1 dimer protein levels were increased in WT mesenteric arterioles treated with 10–7 M aldosterone, and the transglutaminase inhibitor and AT1 blocker blocked this aldosterone-induced formation of AT1 dimer. Treatment with 10–7 M aldosterone for 10 minutes increased the transglutaminase activity by 2.5±0.2 fold in cultured vascular smooth muscle cells and by 1.2±0.1fold in the mesenteric arterioles. These increases were abolished by transglutaminase inhibitors.
Conclusions: Aldosterone produces a nongenomic, endothelium-independent vasoconstrictor effect by enhancing intracellular transglutaminase activity and presumably inducing AT1 dimer formation in mesenteric arterioles.
Time for primary review: 25 days
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  C. A. Lemarie, S. M.C. Simeone, A. Nikonova, T. Ebrahimian, M.-E. Deschenes, T. M. Coffman, P. Paradis, and E. L. Schiffrin Aldosterone-Induced Activation of Signaling Pathways Requires Activity of Angiotensin Type 1a Receptors Circ. Res., October 23, 2009; 105(9): 852 - 859. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Jain, R. C. Campbell, and D. G. Warnock Mineralocorticoid Receptor Blockers and Chronic Kidney Disease Clin. J. Am. Soc. Nephrol., October 1, 2009; 4(10): 1685 - 1691. [Abstract] [Full Text] [PDF]
|
|