Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation Research. 1999;84:752-762

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Leri, A.
Right arrow Articles by Anversa, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Leri, A.
Right arrow Articles by Anversa, P.
Related Collections
Right arrow ACE/Angiotension receptors
Right arrow Genetically altered mice
Right arrow Growth factors/cytokines
(Circulation Research. 1999;84:752-762.)
© 1999 American Heart Association, Inc.

Original Contribution

Overexpression of Insulin-Like Growth Factor-1 Attenuates the Myocyte Renin-Angiotensin System in Transgenic Mice

Annarosa Leri, Yu Liu, Xiaowei Wang, Jan Kajstura, Ashwani Malhotra, Leonard G. Meggs, Piero Anversa

From the Department of Medicine, New York Medical College, Valhalla, NY.

Correspondence and reprint requests to Annarosa Leri, MD, Department of Medicine, Vosburgh Pavilion, Room 302, New York Medical College, Valhalla, NY 10595.

Abstract—Constitutive overexpression of insulin-like growth factor-1 (IGF-1) in myocytes protects them from apoptosis and interferes with myocyte hypertrophy in the normal and pathological heart. Conversely, angiotensin II (Ang II) triggers cell death and promotes myocyte hypertrophy. Moreover, activation of p53 upregulates the cellular renin-angiotensin system (RAS). Therefore, IGF-1 overexpression in FVB.Igf+/- mice may downregulate the local RAS through the attenuation of p53 and p53-inducible genes. On this basis, p53 DNA binding activity to angiotensinogen (Aogen), bax, and the AT1 receptor was determined in left ventricular myocytes from FVB.Igf-/- and FVB.Igf+/- mice. The quantity of Bax, Bcl-2, Aogen, and AT1 receptor in these cells was evaluated. The presence of Mdm2-p53 complexes was also established. Finally, Ang II levels in myocytes were measured. Upregulation of IGF-1 in myocytes was associated with a protein-to-protein interaction between Mdm2 and p53, which attenuated p53 transcriptional activity for bax, Aogen, and AT1 receptor. Similarly, the amount of Bax, Aogen, and AT1 receptor proteins in these cells decreased. In contrast, the expression of Bcl-2 remained constant. The downregulation of Aogen in myocytes from FVB.Igf+/- mice was characterized by a reduction in Ang II. In conclusion, IGF-1 negatively influences the myocyte RAS through the upregulation of Mdm2 and its binding to p53. This may represent the molecular mechanism responsible for the effects of IGF-1 on cell viability and myocyte hypertrophy in the nonpathological and pathological heart in vivo.


Key Words: insulin-like growth factor-1 • p53 • mdm2 • angiotensin II • transgenic mice




This article has been cited by other articles:


Home page
 J EndocrinolHome page
B.-W. Wang, H. Chang, P. Kuan, and K.-G. Shyu
Angiotensin II activates myostatin expression in cultured rat neonatal cardiomyocytes via p38 MAP kinase and myocyte enhance factor 2 pathway
J. Endocrinol., April 1, 2008; 197(1): 85 - 93.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
Z. Ungvari, C. Parrado-Fernandez, A. Csiszar, and R. de Cabo
Mechanisms Underlying Caloric Restriction and Lifespan Regulation: Implications for Vascular Aging
Circ. Res., March 14, 2008; 102(5): 519 - 528.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Cell. Biol.Home page
Y.-Z. Li, D.-Y. Lu, W.-Q. Tan, J.-X. Wang, and P.-F. Li
p53 Initiates Apoptosis by Transcriptionally Targeting the Antiapoptotic Protein ARC
Mol. Cell. Biol., January 15, 2008; 28(2): 564 - 574.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
S. Jesmin, S. Zaedi, N. Shimojo, M. Iemitsu, K. Masuzawa, N. Yamaguchi, C. N. Mowa, S. Maeda, Y. Hattori, and T. Miyauchi
Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts
Am J Physiol Endocrinol Metab, April 1, 2007; 292(4): E1030 - E1040.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
T. T. Nguyen, N. Cao, J. L. Short, and P. J. White
Intravenous Insulin-like Growth Factor-I Receptor Antisense Treatment Reduces Angiotensin Receptor Expression and Function in Spontaneously Hypertensive Rats
J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1171 - 1177.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
A. Toth, P. Nickson, L. L. Qin, and P. Erhardt
Differential Regulation of Cardiomyocyte Survival and Hypertrophy by MDM2, an E3 Ubiquitin Ligase
J. Biol. Chem., February 10, 2006; 281(6): 3679 - 3689.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
P. Anversa
Aging and Longevity: The IGF-1 Enigma
Circ. Res., September 2, 2005; 97(5): 411 - 414.
[Full Text] [PDF]

Home page
 HypertensionHome page
M. Tsuda, M. Iwai, J.-M. Li, H.-S. Li, L.-J. Min, A. Ide, M. Okumura, J. Suzuki, M. Mogi, H. Suzuki, et al.
Inhibitory Effects of AT1 Receptor Blocker, Olmesartan, and Estrogen on Atherosclerosis Via Anti-Oxidative Stress
Hypertension, April 1, 2005; 45(4): 545 - 551.
[Abstract] [Full Text] [PDF]

Home page
 PediatricsHome page
D. B. McElhinney, S. D. Colan, A. M. Moran, D. Wypij, M. Lin, J. A. Majzoub, E. C. Crawford, J. M. Bartlett, E. A. McGrath, and J. W. Newburger
Recombinant Human Growth Hormone Treatment for Dilated Cardiomyopathy in Children
Pediatrics, October 1, 2004; 114(4): e452 - e458.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
D. Torella, M. Rota, D. Nurzynska, E. Musso, A. Monsen, I. Shiraishi, E. Zias, K. Walsh, A. Rosenzweig, M. A. Sussman, et al.
Cardiac Stem Cell and Myocyte Aging, Heart Failure, and Insulin-Like Growth Factor-1 Overexpression
Circ. Res., March 5, 2004; 94(4): 514 - 524.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
B. P. S. Kang, A. Urbonas, A. Baddoo, S. Baskin, A. Malhotra, and L. G. Meggs
IGF-1 inhibits the mitochondrial apoptosis program in mesangial cells exposed to high glucose
Am J Physiol Renal Physiol, November 1, 2003; 285(5): F1013 - F1024.
[Abstract] [Full Text] [PDF]

Home page
 ANN INTERN MEDHome page
R. S. Vasan, L. M. Sullivan, R. B. D'Agostino, R. Roubenoff, T. Harris, D. B. Sawyer, D. Levy, and P. W.F. Wilson
Serum Insulin-like Growth Factor I and Risk for Heart Failure in Elderly Individuals without a Previous Myocardial Infarction: The Framingham Heart Study
Ann Intern Med, October 21, 2003; 139(8): 642 - 648.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
B. P. S. Kang, S. Frencher, V. Reddy, A. Kessler, A. Malhotra, and L. G. Meggs
High glucose promotes mesangial cell apoptosis by oxidant-dependent mechanism
Am J Physiol Renal Physiol, March 1, 2003; 284(3): F455 - F466.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
F. Limana, K. Urbanek, S. Chimenti, F. Quaini, A. Leri, J. Kajstura, B. Nadal-Ginard, S. Izumo, and P. Anversa
bcl-2 overexpression promotes myocyte proliferation
PNAS, April 30, 2002; 99(9): 6257 - 6262.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
S. Welch, D. Plank, S. Witt, B. Glascock, E. Schaefer, S. Chimenti, A. M. Andreoli, F. Limana, A. Leri, J. Kajstura, et al.
Cardiac-Specific IGF-1 Expression Attenuates Dilated Cardiomyopathy in Tropomodulin-Overexpressing Transgenic Mice
Circ. Res., April 5, 2002; 90(6): 641 - 648.
[Abstract] [Full Text] [PDF]

Home page
 Cold Spring Harb Symp Quant BiolHome page
N. WINN, A. PAUL, A. MUSARO, and N. ROSENTHAL
Insulin-like Growth Factor Isoforms in Skeletal Muscle Aging, Regeneration, and Disease
Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 507 - 518.
[Abstract] [PDF]

Home page
 CirculationHome page
D. Li, K. Shinagawa, L. Pang, T. K. Leung, S. Cardin, Z. Wang, and S. Nattel
Effects of Angiotensin-Converting Enzyme Inhibition on the Development of the Atrial Fibrillation Substrate in Dogs With Ventricular Tachypacing-Induced Congestive Heart Failure
Circulation, November 20, 2001; 104(21): 2608 - 2614.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
F. Fiordaliso, A. Leri, D. Cesselli, F. Limana, B. Safai, B. Nadal-Ginard, P. Anversa, and J. Kajstura
Hyperglycemia Activates p53 and p53-Regulated Genes Leading to Myocyte Cell Death
Diabetes, October 1, 2001; 50(10): 2363 - 2375.
[Abstract] [Full Text]

Home page
 HypertensionHome page
M. Galderisi, G. Vitale, G. Lupoli, M. Barbieri, G. Varricchio, C. Carella, O. de Divitiis, and G. Paolisso
Inverse Association Between Free Insulin-Like Growth Factor-1 and Isovolumic Relaxation in Arterial Systemic Hypertension
Hypertension, October 1, 2001; 38(4): 840 - 845.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
M. H. Vickers, B. A. Ikenasio, and B. H. Breier
IGF-I Treatment Reduces Hyperphagia, Obesity, and Hypertension in Metabolic Disorders Induced by Fetal Programming
Endocrinology, September 1, 2001; 142(9): 3964 - 3973.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
J. Kajstura, F. Fiordaliso, A. M. Andreoli, B. Li, S. Chimenti, M. S. Medow, F. Limana, B. Nadal-Ginard, A. Leri, and P. Anversa
IGF-1 Overexpression Inhibits the Development of Diabetic Cardiomyopathy and Angiotensin II-Mediated Oxidative Stress
Diabetes, June 1, 2001; 50(6): 1414 - 1424.
[Abstract] [Full Text]

Home page
 Circ. Res.Home page
L. Barlucchi, A. Leri, D. E. Dostal, F. Fiordaliso, H. Tada, T. H. Hintze, J. Kajstura, B. Nadal-Ginard, and P. Anversa
Canine Ventricular Myocytes Possess a Renin-Angiotensin System That Is Upregulated With Heart Failure
Circ. Res., February 16, 2001; 88(3): 298 - 304.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
A. Frustaci, J. Kajstura, C. Chimenti, I. Jakoniuk, A. Leri, A. Maseri, B. Nadal-Ginard, and P. Anversa
Myocardial Cell Death in Human Diabetes
Circ. Res., December 8, 2000; 87(12): 1123 - 1132.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
A. Leri, F. Fiordaliso, M. Setoguchi, F. Limana, N. H. Bishopric, J. Kajstura, K. Webster, and P. Anversa
Inhibition of p53 Function Prevents Renin-Angiotensin System Activation and Stretch-Mediated Myocyte Apoptosis
Am. J. Pathol., September 1, 2000; 157(3): 843 - 857.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
A. Leri, Y. Liu, B. Li, F. Fiordaliso, A. Malhotra, R. Latini, J. Kajstura, and P. Anversa
Up-Regulation of AT1 and AT2 Receptors in Postinfarcted Hypertrophied Myocytes and Stretch-Mediated Apoptotic Cell Death
Am. J. Pathol., May 1, 2000; 156(5): 1663 - 1672.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
J. Kajstura, B. Pertoldi, A. Leri, C.-A. Beltrami, A. Deptala, Z. Darzynkiewicz, and P. Anversa
Telomere Shortening Is an in Vivo Marker of Myocyte Replication and Aging
Am. J. Pathol., March 1, 2000; 156(3): 813 - 819.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
J. Schaper, A. Elsasser, and S. Kostin
The Role of Cell Death in Heart Failure
Circ. Res., October 29, 1999; 85(9): 867 - 869.
[Full Text] [PDF]

Home page
 Circ. Res.Home page
D. Cesselli, I. Jakoniuk, L. Barlucchi, A. P. Beltrami, T. H. Hintze, B. Nadal-Ginard, J. Kajstura, A. Leri, and P. Anversa
Oxidative Stress-Mediated Cardiac Cell Death Is a Major Determinant of Ventricular Dysfunction and Failure in Dog Dilated Cardiomyopathy
Circ. Res., August 3, 2001; 89(3): 279 - 286.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
S. Welch, D. Plank, S. Witt, B. Glascock, E. Schaefer, S. Chimenti, A. M. Andreoli, F. Limana, A. Leri, J. Kajstura, et al.
Cardiac-Specific IGF-1 Expression Attenuates Dilated Cardiomyopathy in Tropomodulin-Overexpressing Transgenic Mice
Circ. Res., April 5, 2002; 90(6): 641 - 648.
[Abstract] [Full Text] [PDF]


Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 1999 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.