Published online before print September 17, 2009, doi: 10.1161/CIRCRESAHA.109.196576
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Submitted on February 27, 2009
Revised on September 8, 2009
Accepted on September 9, 2009
Aldosterone-Induced Activation of Signaling Pathways Requires Activity of Angiotensin Type 1a Receptors
Catherine A. Lemarié ;
From the Lady Davis Institute for Medical Research (C.A.L., S.M.C.S., A.N., T.E., M.-E.D., P.P., E.L.S.), Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and Division of Nephrology (T.M.C.), Department of Medicine, Duke University, Durham, NC.
* To whom correspondence should be addressed. E-mail: ernesto.schiffrin{at}mcgill.ca.
Rationale: Aldosterone has been shown to induce vascular damage, endothelial dysfunction, and myocardial fibrosis, which depend in part on activation of angiotensin II (Ang II)–mediated pathways. However, mechanisms underlying crosstalk between Ang II type 1 receptor (AT1R) and mineralocorticoid receptors (MRs) are mostly unknown.
Objectives: We tested whether the lack of Ang II type 1a receptor (AT1aR) or Ang II type 1b receptor (AT1bR) would decrease cellular effects induced by aldosterone.
Methods and Results: We examined the effect of Ang II or aldosterone after transfection of mesenteric vascular smooth muscle cells (VSMCs) from C57Bl/6 mice with small interference RNA for AT1aR, AT1bR, or MRs for 48 hours. Ang II and aldosterone separately induced ERK1/2, c-Jun NH2-terminal protein kinase (JNK), and nuclear factor (NF)-
B phosphorylation after a 20-minute stimulation. Small interference RNA for AT1aR downregulated phosphorylation of ERK1/2, JNK, and NF-B after aldosterone stimulation compared to controls. Downregulation of AT1bR or MRs only abolished the activation of NF-B. In VSMCs from C57Bl/6 mice, aldosterone and Ang II induced the activation of the c-fos promoter from 30 minutes to 1 hour. This effect was blocked when using VSMCs from AT1aR knockout mice.
Conclusion: We show for the first time that nongenomic and genomic effects of aldosterone are differentially dependent on activity of both AT1aR and AT1bR. Our data suggest that aldosterone augments AT1R-dependent activation of ERK1/2, JNK, and NF-B in VSMCs. We provide mechanistic understanding and experimental in vitro support for the benefit of combination therapy with dual blockade of AT1R and MRs to treat hypertension and progression of heart failure as reported in clinical studies and animal models.
Key words: aldosterone • AT1R • AT1aR • AT1bR • intracellular signaling