Hypertension. 2005;45:773-779
Published online before print February 7, 2005,
doi: 10.1161/01.HYP.0000154365.30593.d3
(Hypertension. 2005;45:773.)
© 2005 American Heart Association, Inc.
Aldosterone Activates Vascular p38MAP Kinase and NADPH Oxidase Via c-Src
Glaucia E. Callera;
Rhian M. Touyz;
Rita C. Tostes;
Alvaro Yogi;
Ying He;
Sam Malkinson;
Ernesto L. Schiffrin
From CIHR Multidisciplinary Research Group on Hypertension (G.E.C., R.M.T., Y.H., S.M., E.L.S.), Clinical Research Institute of Montreal, University of Montreal, Canada; and the Department of Pharmacology (R.C.T., A.Y.), Institute of Biomedical Sciences, University of Sao Paulo, Brazil.
Correspondence to Glaucia E. Callera, Clinical Research Institute of Montreal, 110 Pine Ave, West Montreal, Quebec H2W 1H7. E-mail callereg{at}ircm.qc.ca
Increasing evidence indicates that aldosterone elicits vascular effects through nongenomic signaling pathways. We tested the hypothesis that aldosterone induces activation of vascular mitogen-activated protein (MAP) kinases and NADPH oxidase via c-Src–dependent mechanisms in vascular smooth muscle cells (VSMCs). Aldosterone effects on activation of c-Src, p38MAP kinase, and NADPH oxidase, and incorporation of [3H]proline, an index of collagen synthesis, were assessed in cultured rat VSMCs. Studies were performed in the absence and presence of eplerenone, a selective mineralocorticoid receptor blocker, PP2, a selective Src inhibitor, and SB212190, a selective p38MAPK inhibitor. Phosphorylation of c-Src was dose-dependently increased by aldosterone, with maximal responses obtained at 10–7 mol/L. Aldosterone increased p38MAP kinase phosphorylation, NAD(P)H oxidase activation, and [3H]proline incorporation. These responses were abrogated by eplerenone and almost abolished by PP2. Aldosterone-stimulated incorporation of [3H]proline was significantly reduced by SB212190, indicating that p38MAP kinase plays a role in profibrotic actions of aldosterone. To unambiguously demonstrate the importance of aldosterone in c-Src signaling, VSMCs from c-Src+/+ and c-Src+/– mice were also studied. Aldosterone increased phosphorylation of c-Src, p38MAP kinase, and cortactin, a Src-specific substrate, in c-Src+/+ VSMCs, but not in c-Src-deficient cells. Taken together, our findings demonstrate that nongenomic signaling by aldosterone occurs through c-Src–dependent pathways. These processes may play an important role in profibrotic actions of aldosterone.
Key Words: aldosterone • mineralocorticoids • oxidative stress • vasculature • signal transduction • collagen
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|
|
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150(11):
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|
|
|
|
|
|
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|
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|
|
|
|
|
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|
|
|
|
|
|
|
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150(4):
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|
|
|
|
|
|
|
J. Goto, F. Otsuka, M. Yamashita, J. Suzuki, H. Otani, H. Takahashi, T. Miyoshi, Y. Mimura, T. Ogura, and H. Makino
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April 1, 2009;
296(4):
E904 - E916.
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[Full Text]
[PDF]
|
|
|
|
|
|
|
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Aldosterone activates endothelial exocytosis
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106(10):
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|
|
|
|
|
|
|
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296(2):
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|
|
|
|
|
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|
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|
|
|
|
|
|
|
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149(10):
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
C. Zanchi, C. Zoja, M. Morigi, F. Valsecchi, X. Y. Liu, D. Rottoli, M. Locatelli, S. Buelli, A. Pezzotta, P. Mapelli, et al.
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1460 - 1469.
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|
|
|
|
|
|
|
B. Sontia, A. C.I. Montezano, T. Paravicini, F. Tabet, and R. M. Touyz
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51(4):
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|
|
|
|
|
|
|
F. Iwashima, T. Yoshimoto, I. Minami, M. Sakurada, Y. Hirono, and Y. Hirata
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149(3):
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|
|
|
|
|
|
|
E. L. Schiffrin
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|
|
|
|
|
|
|
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294(2):
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|
|
|
|
|
|
|
N. J. Brown
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51(2):
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|
|
|
|
|
|
|
H. Hitomi, H. Kiyomoto, A. Nishiyama, T. Hara, K. Moriwaki, K. Kaifu, G. Ihara, Y. Fujita, T. Ugawa, and M. Kohno
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|
|
|
|
|
|
|
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27(9):
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|
|
|
|
|
|
|
F. Nietlispach, B. Julius, R. Schindler, A. Bernheim, C. Binkert, W. Kiowski, and H. P. Brunner-La Rocca
Influence of Acute and Chronic Mineralocorticoid Excess on Endothelial Function in Healthy Men
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July 1, 2007;
50(1):
82 - 88.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Otani, F. Otsuka, K. Inagaki, M. Takeda, T. Miyoshi, J. Suzuki, T. Mukai, T. Ogura, and H. Makino
Antagonistic effects of bone morphogenetic protein-4 and -7 on renal mesangial cell proliferation induced by aldosterone through MAPK activation
Am J Physiol Renal Physiol,
May 1, 2007;
292(5):
F1513 - F1525.
[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]
|
|
|
|
|
|
|
O. Jung, S. L. Marklund, N. Xia, R. Busse, and R. P. Brandes
Inactivation of Extracellular Superoxide Dismutase Contributes to the Development of High-Volume Hypertension
Arterioscler Thromb Vasc Biol,
March 1, 2007;
27(3):
470 - 477.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-K. Park, R. Fischer, R. Dechend, E. Shagdarsuren, A. Gapeljuk, M. Wellner, S. Meiners, P. Gratze, N. Al-Saadi, S. Feldt, et al.
p38 Mitogen-Activated Protein Kinase Inhibition Ameliorates Angiotensin II-Induced Target Organ Damage
Hypertension,
March 1, 2007;
49(3):
481 - 489.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Yu, Y.-M. Kang, Z.-H. Zhang, S.-G. Wei, Y. Chu, R. M. Weiss, and R. B. Felder
Increased Cyclooxygenase-2 Expression in Hypothalamic Paraventricular Nucleus in Rats With Heart Failure: Role of Nuclear Factor {kappa}B
Hypertension,
March 1, 2007;
49(3):
511 - 518.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Gros, Q. Ding, S. Armstrong, C. O'Neil, J. G. Pickering, and R. D. Feldman
Rapid effects of aldosterone on clonal human vascular smooth muscle cells
Am J Physiol Cell Physiol,
February 1, 2007;
292(2):
C788 - C794.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Shibata, M. Nagase, S. Yoshida, H. Kawachi, and T. Fujita
Podocyte as the Target for Aldosterone: Roles of Oxidative Stress and Sgk1
Hypertension,
February 1, 2007;
49(2):
355 - 364.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Bedard and K.-H. Krause
The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology
Physiol Rev,
January 1, 2007;
87(1):
245 - 313.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. M. Thobe, M. Frink, M. A. Choudhry, M. G. Schwacha, K. I. Bland, and I. H. Chaudry
Src family kinases regulate p38 MAPK-mediated IL-6 production in Kupffer cells following hypoxia
Am J Physiol Cell Physiol,
September 1, 2006;
291(3):
C476 - C482.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Marumo, H. Uchimura, M. Hayashi, K. Hishikawa, and T. Fujita
Aldosterone Impairs Bone Marrow-Derived Progenitor Cell Formation
Hypertension,
September 1, 2006;
48(3):
490 - 496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Johar, A. C. Cave, A. Narayanapanicker, D. J. Grieve, and A. M. Shah
Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase
FASEB J,
July 1, 2006;
20(9):
1546 - 1548.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Kobayashi, K. Yoshida, S. Nakano, T. Ohno, T. Honda, Y. Tsubokou, and H. Matsuoka
Cardioprotective Mechanisms of Eplerenone on Cardiac Performance and Remodeling in Failing Rat Hearts
Hypertension,
April 1, 2006;
47(4):
671 - 679.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. L. Schiffrin
Effects of Aldosterone on the Vasculature
Hypertension,
March 1, 2006;
47(3):
312 - 318.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Miyata, M. Rahman, T. Shokoji, Y. Nagai, G.-X. Zhang, G.-P. Sun, S. Kimura, T. Yukimura, H. Kiyomoto, M. Kohno, et al.
Aldosterone Stimulates Reactive Oxygen Species Production through Activation of NADPH Oxidase in Rat Mesangial Cells
J. Am. Soc. Nephrol.,
October 1, 2005;
16(10):
2906 - 2912.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Nagai, K. Miyata, G.-P. Sun, M. Rahman, S. Kimura, A. Miyatake, H. Kiyomoto, M. Kohno, Y. Abe, M. Yoshizumi, et al.
Aldosterone Stimulates Collagen Gene Expression and Synthesis Via Activation of ERK1/2 in Rat Renal Fibroblasts
Hypertension,
October 1, 2005;
46(4):
1039 - 1045.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Ishizawa, Y. Izawa, H. Ito, C. Miki, K. Miyata, Y. Fujita, Y. Kanematsu, K. Tsuchiya, T. Tamaki, A. Nishiyama, et al.
Aldosterone Stimulates Vascular Smooth Muscle Cell Proliferation Via Big Mitogen-Activated Protein Kinase 1 Activation
Hypertension,
October 1, 2005;
46(4):
1046 - 1052.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. E. Callera, A. C. I. Montezano, A. Yogi, R. C. Tostes, Y. He, E. L. Schiffrin, and R. M. Touyz
c-Src-Dependent Nongenomic Signaling Responses to Aldosterone Are Increased in Vascular Myocytes From Spontaneously Hypertensive Rats
Hypertension,
October 1, 2005;
46(4):
1032 - 1038.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Wehling
Rapid Effects of Aldosterone: Relevant in Cardiac Ischemia?
Hypertension,
July 1, 2005;
46(1):
27 - 28.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. C. Blaxall, J. M. Miano, and B. C. Berk
Angiotensin II: A Devious Activator of Mineralocorticoid Receptor-Dependent Gene Expression
Circ. Res.,
April 1, 2005;
96(6):
610 - 611.
[Full Text]
[PDF]
|
|
|
