|
 |
|
|||||||
|
|||||||||
© 2001 by the American Diabetes Association, Inc.
Hyperglycemia Activates p53 and p53-Regulated Genes Leading to Myocyte Cell Death
1 Department of Medicine, New York Medical College, Valhalla, New York
2 Department of Dermatology, New York Medical College, Valhalla, New York
3 Mario Negri Institute of Pharmacological Research, Milan, Italy
To determine whether enzymatic p53 glycosylation leads to angiotensin II formation followed by p53 phosphorylation, prolonged activation of the renin-angiotensin system, and apoptosis, ventricular myocytes were exposed to levels of glucose mimicking diabetic hyperglycemia. At a high glucose concentration, O-glycosylation of p53 occurred between 10 and 20 min, reached its peak at 1 h, and then decreased with time. Angiotensin II synthesis increased at 45 min and 1 h, resulting in p38 mitogen-activated protein (MAP) kinase–driven p53 phosphorylation at Ser 390. p53 phosphorylation was absent at the early time points, becoming evident at 1 h, and increasing progressively from 3 h to 4 days. Phosphorylated p53 at Ser 18 and activated c-Jun NH2-terminal kinases were identified with hyperglycemia, whereas extracellular signal-regulated kinase was not phosphorylated. Upregulation of p53 was associated with an accumulation of angiotensinogen and AT1 and enhanced production of angiotensin II. Bax quantity also increased. These multiple adaptations paralleled the concentrations of glucose in the medium and the duration of the culture. Myocyte death by apoptosis directly correlated with glucose and angiotensin II levels. Inhibition of O-glycosylation prevented the initial synthesis of angiotensin II, p53, and p38-MAP kinase (MAPK) phosphorylation and apoptosis. AT1 blockade had no influence on O-glycosylation of p53, but it interfered with p53 phosphorylation; losartan also prevented phosphorylation of p38-MAPK by angiotensin II. Inhibition of p38-MAPK mimicked at a more distal level the consequences of losartan. In conclusion, these in vitro results support the notion that hyperglycemia with diabetes promotes myocyte apoptosis mediated by activation of p53 and effector responses involving the local renin-angiotensin system.
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  E. N. Lavrentyev, A. M. Estes, and K. U. Malik Mechanism of High Glucose Induced Angiotensin II Production in Rat Vascular Smooth Muscle Cells Circ. Res., August 31, 2007; 101(5): 455 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Luptak, J. Yan, L. Cui, M. Jain, R. Liao, and R. Tian Long-Term Effects of Increased Glucose Entry on Mouse Hearts During Normal Aging and Ischemic Stress Circulation, August 21, 2007; 116(8): 901 - 909. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kobayashi, K. Mao, H. Zheng, X. Wang, C. Patterson, T. D. O'Connell, and Q. Liang Diminished GATA4 Protein Levels Contribute to Hyperglycemia-induced Cardiomyocyte Injury J. Biol. Chem., July 27, 2007; 282(30): 21945 - 21952. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Galderisi Diastolic Dysfunction and Diabetic Cardiomyopathy: Evaluation by Doppler Echocardiography J. Am. Coll. Cardiol., October 17, 2006; 48(8): 1548 - 1551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Rota, N. LeCapitaine, T. Hosoda, A. Boni, A. De Angelis, M. E. Padin-Iruegas, G. Esposito, S. Vitale, K. Urbanek, C. Casarsa, et al. Diabetes Promotes Cardiac Stem Cell Aging and Heart Failure, Which Are Prevented by Deletion of the p66shc Gene Circ. Res., July 7, 2006; 99(1): 42 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Susztak, A. C. Raff, M. Schiffer, and E. P. Bottinger Glucose-Induced Reactive Oxygen Species Cause Apoptosis of Podocytes and Podocyte Depletion at the Onset of Diabetic Nephropathy Diabetes, January 1, 2006; 55(1): 225 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. I. Arroba, L. M. Frago, J. Argente, and J. A. Chowen Activation of Caspase 8 in the Pituitaries of Streptozotocin-Induced Diabetic Rats: Implication in Increased Apoptosis of Lactotrophs Endocrinology, October 1, 2005; 146(10): 4417 - 4424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ghosh, T. Pulinilkunnil, G. Yuen, G. Kewalramani, D. An, D. Qi, A. Abrahani, and B. Rodrigues Cardiomyocyte apoptosis induced by short-term diabetes requires mitochondrial GSH depletion Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H768 - H776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. W. Braithwaite, J. A. Royds, and P. Jackson The p53 story: layers of complexity Carcinogenesis, July 1, 2005; 26(7): 1161 - 1169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Hu, D. Belke, J. Suarez, E. Swanson, R. Clark, M. Hoshijima, and W. H. Dillmann Adenovirus-Mediated Overexpression of O-GlcNAcase Improves Contractile Function in the Diabetic Heart Circ. Res., May 13, 2005; 96(9): 1006 - 1013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Fiordaliso, S. Chimenti, L. Staszewsky, A. Bai, E. Carlo, I. Cuccovillo, M. Doni, M. Mengozzi, R. Tonelli, P. Ghezzi, et al. A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia-reperfusion injury PNAS, February 8, 2005; 102(6): 2046 - 2051. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Modesti, I. Bertolozzi, T. Gamberi, M. Marchetta, C. Lumachi, M. Coppo, F. Moroni, T. Toscano, G. Lucchese, G. F. Gensini, et al. Hyperglycemia Activates JAK2 Signaling Pathway in Human Failing Myocytes via Angiotensin II-Mediated Oxidative Stress Diabetes, February 1, 2005; 54(2): 394 - 401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-S. Chen, Y.-X. Shan, T.-L. Yang, H.-D. Lin, J.-W. Chen, S.-J. Lin, and P. H. Wang Insulin Deficiency Downregulated Heat Shock Protein 60 and IGF-1 Receptor Signaling in Diabetic Myocardium Diabetes, January 1, 2005; 54(1): 175 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-B. Catrina, K. Okamoto, T. Pereira, K. Brismar, and L. Poellinger Hyperglycemia Regulates Hypoxia-Inducible Factor-1{alpha} Protein Stability and Function Diabetes, December 1, 2004; 53(12): 3226 - 3232. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. S. Lim, R. J. MacFadyen, and G. Y. H. Lip Diabetes Mellitus, the Renin-Angiotensin-Aldosterone System, and the Heart Arch Intern Med, September 13, 2004; 164(16): 1737 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Y. Fang, J. B. Prins, and T. H. Marwick Diabetic Cardiomyopathy: Evidence, Mechanisms, and Therapeutic Implications Endocr. Rev., August 1, 2004; 25(4): 543 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. LaDisa Jr., J. G. Krolikowski, P. S. Pagel, D. C. Warltier, and J. R. Kersten Cardioprotection by glucose-insulin-potassium: dependence on KATP channel opening and blood glucose concentration before ischemia Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H601 - H607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Raimondi, P. De Paoli, E. Mannucci, G. Lonardo, L. Sartiani, G. Banchelli, R. Pirisino, A. Mugelli, and E. Cerbai Restoration of Cardiomyocyte Functional Properties by Angiotensin II Receptor Blockade in Diabetic Rats Diabetes, July 1, 2004; 53(7): 1927 - 1933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Pang, P. Bounelis, J. C. Chatham, and R. B. Marchase Hexosamine Pathway Is Responsible for Inhibition by Diabetes of Phenylephrine-Induced Inotropy Diabetes, April 1, 2004; 53(4): 1074 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
B. Husse, A. Sopart, and G. Isenberg Cyclical mechanical stretch-induced apoptosis in myocytes from young rats but necrosis in myocytes from old rats Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1521 - H1527. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Picano Diabetic cardiomyopathy: the importance of being earliest J. Am. Coll. Cardiol., August 6, 2003; 42(3): 454 - 457. [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Privratsky, L. E. Wold, J. R. Sowers, M. T. Quinn, and J. Ren AT1 Blockade Prevents Glucose-Induced Cardiac Dysfunction in Ventricular Myocytes: Role of the AT1 Receptor and NADPH Oxidase Hypertension, August 1, 2003; 42(2): 206 - 212. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hiromura, C. H. Choi, N. A. Sabourin, H. Jones, D. Bachvarov, and A. Usheva YY1 Is Regulated by O-Linked N-Acetylglucosaminylation (O-GlcNAcylation) J. Biol. Chem., April 11, 2003; 278(16): 14046 - 14052. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
B. Nadal-Ginard, J. Kajstura, A. Leri, and P. Anversa Myocyte Death, Growth, and Regeneration in Cardiac Hypertrophy and Failure Circ. Res., February 7, 2003; 92(2): 139 - 150. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |