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Hyperglycemia Activates p53 and p53-Regulated Genes Leading to Myocyte Cell Death
Ist Teil von
Diabetes (New York, N.Y.), 2001-10, Vol.50 (10), p.2363-2375
Ort / Verlag
Alexandria, VA: American Diabetes Association
Erscheinungsjahr
2001
Quelle
MEDLINE
Beschreibungen/Notizen
Hyperglycemia Activates p53 and p53-Regulated Genes Leading to Myocyte Cell Death
Fabio Fiordaliso 1 3 ,
Annarosa Leri 1 ,
Daniela Cesselli 2 ,
Federica Limana 1 3 ,
Bijan Safai 2 ,
Bernardo Nadal-Ginard 1 ,
Piero Anversa 1 and
Jan Kajstura 1
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
Abstract
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 NH 2 -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 AT 1 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. AT 1 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.
Footnotes
Address correspondence and reprint requests to Jan Kajstura, Department of Medicine, New York Medical College, Vosburgh Pavilion,
Room 302A, Valhalla, NY 10595. E-mail: jan.kajstura.{at}nymc.edu .
Received for publication 1 December 2000 and accepted in revised form 18 July 2001.
Aogen, angiotensinogen; Ang II, angiotensin II; ATF-2, activating transcription factor-2; BAG, benzyl 2-acetamido-2-deoxy-α- d -galactopyranoside; CM, conditioned medium; ELISA, enzyme-linked immunosorbent assay; ERK, extracellular signal-regulated
kinase; GlcNAc, N-acetylglucosamine; HRP, horseradish-peroxidase; JNK, c-Jun NH 2 -terminal kinase; MAP, mitogen-activated protein; MAPK, MAP kinase; PI, propidium iodide; PMSF, phenylmethylsulfonyl fluoride;
RAS, renin-angiotensin system; SFM, serum-free medium; TdT, terminal deoxynucleotidyl transferase; TFA, trifluoroacetic acid;
TBST, Tris-buffered saline/Tween 20.