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GSK3β and MCL-1 mediate cardiomyocyte apoptosis in response to high glucose

Dongmei Su1,2, Jing Zhao3, Shanshan Hu4

  • 1Department of Genetics, Center for Genetics, Health Department, National Research Institute for Family Planning, 12, Dahuisi Road, Haidian, Beijing, 100081, China.

Histochemistry and Cell Biology
|June 15, 2019
PubMed

Insights

Gestational diabetes increases congenital heart defect risk. High glucose induces cardiomyocyte apoptosis via decreased GSK3β (Ser9) phosphorylation and MCL-1 expression, a pathway targeted by SC79.

Area of Science:

  • Cardiovascular Biology
  • Developmental Biology
  • Endocrinology

Background:

  • Gestational diabetes mellitus (GDM) is a significant risk factor for congenital heart defects (CHDs).
  • Hyperglycemia in GDM can lead to decreased myocardial cells and increased apoptosis, contributing to heart abnormalities.
  • The precise mechanisms of high glucose-induced cardiomyocyte apoptosis remain incompletely understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying high glucose-induced cardiomyocyte apoptosis.
  • To investigate the roles of GSK3β (glycogen synthase kinase 3 beta) and MCL-1 (myeloid cell leukemia 1) in this process.
  • To explore potential therapeutic targets for maternal diabetes-induced cardiac abnormalities.

Main Methods:

  • In vitro and in vivo studies using cardiomyocytes and heart tissues from diabetic rat models.
  • Assessment of GSK3β phosphorylation at Ser9 in response to high glucose.
  • Evaluation of the effects of SC79 (Akt pathway activator) and SB216763 (GSK3β inhibitor) on cardiomyocyte apoptosis.
  • Analysis of MCL-1 expression and the impact of its overexpression.

Main Results:

  • High glucose significantly decreased GSK3β phosphorylation on Ser9 in cardiomyocytes, both in vitro and in vivo.
  • SC79 treatment restored GSK3β (Ser9) phosphorylation, while SB216763 exacerbated high glucose-induced apoptosis.
  • A decrease in the anti-apoptotic protein MCL-1 was observed and linked to GSK3β-mediated apoptosis.
  • Overexpression of MCL-1 partially protected cardiomyocytes against high glucose-induced apoptosis.

Conclusions:

  • GSK3β signaling, specifically reduced phosphorylation at Ser9, plays a critical role in high glucose-induced cardiomyocyte apoptosis.
  • MCL-1 acts as a downstream effector in the GSK3β-mediated apoptotic pathway.
  • Targeting the GSK3β/MCL-1 axis may offer therapeutic strategies for preventing cardiac defects associated with maternal diabetes.
Keywords:
Cardiomyocyte apoptosisCongenital heart diseaseGSK3βHigh glucoseMCL-1

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