Published online before print August 4, 2005, doi: 10.1161/01.RES.0000180753.63183.95
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 7, 2005
Revised on July 27, 2005
Accepted on July 27, 2005
Aldosterone and Angiotensin II Synergistically Induce Mitogenic Response in Vascular Smooth Muscle Cells
Li-Juan Min ;
From the Department of Molecular and Cellular Biology, Division of Medical Biochemistry and Cardiovascular Biology, Ehime University School of Medicine, Tohon, Japan.
* To whom correspondence should be addressed. E-mail: horiuchi{at}m.ehime-u.ac.jp.
Interaction between aldosterone (Aldo) and angiotensin II (Ang II) in the cardiovascular system has been highlighted; however, its detailed signaling mechanism is poorly understood. Here, we examined the cross-talk of growth-promoting signaling between Aldo and Ang II in vascular smooth muscle cells (VSMC). Treatment with a lower dose of Aldo (10-12 mol/L) and with a lower dose of Ang II (10-10 mol/L) significantly enhanced DNA synthesis, whereas Aldo or Ang II alone at these doses did not affect VSMC proliferation. This effect of a combination of Aldo and Ang II was markedly inhibited by a selective AT1 receptor blocker, olmesartan, a mineralocorticoid receptor antagonist, spironolactone, an MEK inhibitor, PD98059, or an EGF receptor tyrosine kinase inhibitor, AG1478. Treatment with Aldo together with Ang II, even at noneffective doses, respectively, synergistically increased extracellular signal-regulated kinase (ERK) activation, reaching 2 peaks at 10 to 15 minutes and 2 to 4 hours. The early ERK peak was effectively blocked by olmesartan or an EGF receptor kinase inhibitor, AG1478, but not by spironolactone, whereas the late ERK peak was completely inhibited by not only olmesartan, but also spironolactone. Combined treatment with Aldo and Ang II attenuated mitogen-activated protein kinase phosphatase-1 (MKP-1) expression and increased Ki-ras2A expression. The late ERK peak was not observed in VSMC treated with Ki-ras2A-siRNA. Interestingly, the decrease in MKP-1 expression and the increase in Ki-ras2A expression were restored by PD98059 or AG1478. These results suggest that Aldo exerts a synergistic mitogenic effect with Ang II and support the notion that blockade of both Aldo and Ang II could be more effective to prevent vascular remodeling.
Key words: aldosterone • angiotensin II • vascular smooth muscle cells • mitogen-activated protein kinases • signal transduction
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]
|
|
|
|
 |
|
 Y. Minoura, H. Onimaru, K. Iigaya, I. Homma, and Y. Kobayashi Electrophysiological responses of sympathetic preganglionic neurons to ANG II and aldosterone Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R699 - R706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Luther, Z. Wang, J. Ma, N. Makhanova, H.-S. Kim, and N. J. Brown Endogenous Aldosterone Contributes to Acute Angiotensin II-Stimulated Plasminogen Activator Inhibitor-1 and Preproendothelin-1 Expression in Heart But Not Aorta Endocrinology, May 1, 2009; 150(5): 2229 - 2236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Fujita, M. Mogi, L.-J. Min, J. Iwanami, K. Tsukuda, A. Sakata, H. Okayama, M. Iwai, C. Nahmias, J. Higaki, et al. Attenuation of Cuff-Induced Neointimal Formation by Overexpression of Angiotensin II Type 2 Receptor-Interacting Protein 1 Hypertension, April 1, 2009; 53(4): 688 - 693. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Jeong, D. F. Chaupin, K. Matsushita, M. Yamakuchi, S. J. Cameron, C. N. Morrell, and C. J. Lowenstein Aldosterone activates endothelial exocytosis PNAS, March 10, 2009; 106(10): 3782 - 3787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.C. Montezano, G.E. Callera, A. Yogi, Y. He, R.C. Tostes, G. He, E.L. Schiffrin, and R.M. Touyz Aldosterone and Angiotensin II Synergistically Stimulate Migration in Vascular Smooth Muscle Cells Through c-Src-Regulated Redox-Sensitive RhoA Pathways Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1511 - 1518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Yamada, M. Kushibiki, T. Osanai, H. Tomita, and K. Okumura Vasoconstrictor effect of aldosterone via angiotensin II type 1 (AT1) receptor: possible role of AT1 receptor dimerization Cardiovasc Res, July 1, 2008; 79(1): 169 - 178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Grossmann, R. Freudinger, S. Mildenberger, B. Husse, and M. Gekle EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions J. Biol. Chem., March 14, 2008; 283(11): 7109 - 7116. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin New Twist to the Role of the Renin-Angiotensin System in Heart Failure: Aldosterone Upregulates Renin-Angiotensin System Components in the Brain Hypertension, March 1, 2008; 51(3): 622 - 623. [Full Text] [PDF]
|
|
|
|
|
|
N. J. Brown Aldosterone and Vascular Inflammation Hypertension, February 1, 2008; 51(2): 161 - 167. [Full Text] [PDF]
|
|
|
|
|
|
L.-J. Min, M. Mogi, J. Iwanami, J.-M. Li, A. Sakata, T. Fujita, K. Tsukuda, M. Iwai, and M. Horiuchi Cross-talk between aldosterone and angiotensin II in vascular smooth muscle cell senescence Cardiovasc Res, December 1, 2007; 76(3): 506 - 516. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Casal, S. Ryser, A. M. Capponi, and C. F. Wang-Buholzer Angiotensin II-Induced Mitogen-Activated Protein Kinase Phosphatase-1 Expression in Bovine Adrenal Glomerulosa Cells: Implications in Mineralocorticoid Biosynthesis Endocrinology, November 1, 2007; 148(11): 5573 - 5581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Cooper, A. Whaley-Connell, J. Habibi, Y. Wei, G. Lastra, C. Manrique, S. Stas, and J. R. Sowers Renin-angiotensin-aldosterone system and oxidative stress in cardiovascular insulin resistance Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2009 - H2023. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Grossmann, A. W. Krug, R. Freudinger, S. Mildenberger, K. Voelker, and M. Gekle Aldosterone-induced EGFR expression: interaction between the human mineralocorticoid receptor and the human EGFR promoter Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1790 - E1800. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hirono, T. Yoshimoto, N. Suzuki, T. Sugiyama, M. Sakurada, S. Takai, N. Kobayashi, M. Shichiri, and Y. Hirata Angiotensin II Receptor Type 1-Mediated Vascular Oxidative Stress and Proinflammatory Gene Expression in Aldosterone-Induced Hypertension: The Possible Role of Local Renin-Angiotensin System Endocrinology, April 1, 2007; 148(4): 1688 - 1696. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Nakamura, S. Suzuki, T. Suzuki, K. Ono, I. Miura, F. Satoh, T. Moriya, H. Saito, S. Yamada, S. Ito, et al. MDM2: A Novel Mineralocorticoid-Responsive Gene Involved in Aldosterone-Induced Human Vascular Structural Remodeling Am. J. Pathol., August 1, 2006; 169(2): 362 - 371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Suzuki, M. Iwai, M. Mogi, A. Oshita, T. Yoshii, J. Higaki, and M. Horiuchi Eplerenone With Valsartan Effectively Reduces Atherosclerotic Lesion by Attenuation of Oxidative Stress and Inflammation Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 917 - 921. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Dorrance, N. C. Rupp, and E. F. Nogueira Mineralocorticoid Receptor Activation Causes Cerebral Vessel Remodeling and Exacerbates the Damage Caused by Cerebral Ischemia Hypertension, March 1, 2006; 47(3): 590 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Schiffrin Effects of Aldosterone on the Vasculature Hypertension, March 1, 2006; 47(3): 312 - 318. [Full Text] [PDF]
|
|
|
|
|
|
P. J. Fuller and M. J. Young Mechanisms of Mineralocorticoid Action Hypertension, December 1, 2005; 46(6): 1227 - 1235. [Abstract] [Full Text] [PDF]
|
|