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Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors.

Publication ,  Journal Article
Lemarié, CA; Simeone, SMC; Nikonova, A; Ebrahimian, T; Deschênes, M-E; Coffman, TM; Paradis, P; Schiffrin, EL
Published in: Circ Res
October 23, 2009

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 (AT(1)R) and mineralocorticoid receptor (MR) are mostly unknown. OBJECTIVES: We tested whether the lack of Ang II type 1a receptor (AT(1a)R) or Ang II type 1b receptor (AT(1b)R) 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 AT(1a)R, AT(1b)R, or MR for 48 hours. Ang II and aldosterone separately induced ERK1/2, c-Jun NH2-terminal protein kinase (JNK), and nuclear factor (NF)-kappaB phosphorylation after a 20-minute stimulation. Small interference RNA for AT(1a)R downregulated phosphorylation of ERK1/2, JNK, and NF-kappaB after aldosterone stimulation compared to controls. Downregulation of AT(1b)R or MR only abolished the activation of NF-kappaB. 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 AT(1a)R knockout mice. CONCLUSION: We show for the first time that nongenomic and genomic effects of aldosterone are differentially dependent on activity of both AT(1a)R and AT(1b)R. Our data suggest that aldosterone augments AT(1)R-dependent activation of ERK1/2, JNK, and NF-kappaB in VSMCs. We provide mechanistic understanding and experimental in vitro support for the benefit of combination therapy with dual blockade of AT(1)R and MR to treat hypertension and progression of heart failure as reported in clinical studies and animal models.

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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

October 23, 2009

Volume

105

Issue

9

Start / End Page

852 / 859

Location

United States

Related Subject Headings

  • Transfection
  • Time Factors
  • Signal Transduction
  • Receptors, Mineralocorticoid
  • Receptor, Angiotensin, Type 1
  • Receptor Cross-Talk
  • RNA Interference
  • Proto-Oncogene Proteins c-fos
  • Phosphorylation
  • NF-kappa B
 

Citation

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Lemarié, C. A., Simeone, S. M. C., Nikonova, A., Ebrahimian, T., Deschênes, M.-E., Coffman, T. M., … Schiffrin, E. L. (2009). Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors. Circ Res, 105(9), 852–859. https://doi.org/10.1161/CIRCRESAHA.109.196576
Lemarié, Catherine A., Stefania M. C. Simeone, Anna Nikonova, Talin Ebrahimian, Marie-Eve Deschênes, Thomas M. Coffman, Pierre Paradis, and Ernesto L. Schiffrin. “Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors.Circ Res 105, no. 9 (October 23, 2009): 852–59. https://doi.org/10.1161/CIRCRESAHA.109.196576.
Lemarié CA, Simeone SMC, Nikonova A, Ebrahimian T, Deschênes M-E, Coffman TM, et al. Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors. Circ Res. 2009 Oct 23;105(9):852–9.
Lemarié, Catherine A., et al. “Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors.Circ Res, vol. 105, no. 9, Oct. 2009, pp. 852–59. Pubmed, doi:10.1161/CIRCRESAHA.109.196576.
Lemarié CA, Simeone SMC, Nikonova A, Ebrahimian T, Deschênes M-E, Coffman TM, Paradis P, Schiffrin EL. Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors. Circ Res. 2009 Oct 23;105(9):852–859.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

October 23, 2009

Volume

105

Issue

9

Start / End Page

852 / 859

Location

United States

Related Subject Headings

  • Transfection
  • Time Factors
  • Signal Transduction
  • Receptors, Mineralocorticoid
  • Receptor, Angiotensin, Type 1
  • Receptor Cross-Talk
  • RNA Interference
  • Proto-Oncogene Proteins c-fos
  • Phosphorylation
  • NF-kappa B