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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

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Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death

F Fiordaliso1, A Leri, D Cesselli

  • 1Department of Medicine, New York Medical College, Valhalla, New York 10595, USA.

Diabetes
|September 28, 2001
PubMed

Insights

Diabetic hyperglycemia triggers p53 glycosylation, leading to angiotensin II production, p53 phosphorylation, and myocyte apoptosis via the renin-angiotensin system. Inhibiting O-glycosylation or AT(1) blockade prevents these damaging effects.

Area of Science:

  • Cardiovascular Biology
  • Metabolic Disease Research
  • Molecular Cell Biology

Background:

  • Diabetic hyperglycemia is a major risk factor for cardiovascular complications.
  • The renin-angiotensin system (RAS) plays a critical role in cardiovascular homeostasis.
  • p53 is a tumor suppressor protein involved in cellular stress responses and apoptosis.

Purpose of the Study:

  • To investigate the role of enzymatic p53 glycosylation in angiotensin II formation and subsequent p53 phosphorylation under hyperglycemic conditions.
  • To elucidate the involvement of the renin-angiotensin system (RAS) in hyperglycemia-induced myocyte apoptosis.
  • To determine the signaling pathways linking hyperglycemia, p53 activation, and myocyte death.

Main Methods:

  • Ventricular myocytes were exposed to varying glucose concentrations to mimic diabetic hyperglycemia.
  • p53 O-glycosylation, angiotensin II synthesis, and p53 phosphorylation were measured over time.
  • Western blotting was used to detect phosphorylated p53, activated kinases (p38 MAPK, JNK, ERK), angiotensinogen, AT(1), and Bax.
  • Inhibition of O-glycosylation, AT(1) blockade (losartan), and p38-MAPK inhibition were employed to assess causal relationships.

Main Results:

  • High glucose induced O-glycosylation of p53, followed by increased angiotensin II synthesis and p38 MAPK-driven p53 phosphorylation.
  • Hyperglycemia led to p53 upregulation, accumulation of angiotensinogen and AT(1), enhanced angiotensin II production, and increased Bax levels.
  • Myocyte apoptosis directly correlated with glucose and angiotensin II levels.
  • Inhibition of O-glycosylation or AT(1) blockade prevented angiotensin II synthesis, p53 phosphorylation, and apoptosis.
  • p38-MAPK inhibition mimicked the effects of AT(1) blockade, suggesting its downstream role.

Conclusions:

  • Hyperglycemia in diabetes promotes myocyte apoptosis through p53 activation.
  • The local renin-angiotensin system is a key mediator in hyperglycemia-induced p53 activation and apoptosis.
  • Targeting O-glycosylation or the AT(1) receptor may offer therapeutic strategies for diabetic cardiomyopathy.

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