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Metformin differentially activates ER stress signaling pathways without inducing apoptosis
Thomas Quentin1, Michael Steinmetz, Andrea Poppe
1Department of Pediatric Cardiology and Pediatric Intensive Care Medicine, University of Göttingen, Göttingen, Germany. thomas.quentin@med.uni-goettingen.de
Disease Models & Mechanisms
|November 24, 2011
Summary
Metformin activates specific endoplasmic reticulum stress pathways in heart cells, upregulating CHOP protein without causing cell death. This suggests a novel mechanism for metformin's potential cardioprotective effects in diabetes.
Area of Science:
- Cardiovascular Research
- Endocrinology
- Cellular Biology
Background:
- Endoplasmic reticulum stress signaling (ERSS) is implicated in diabetes and heart disease pathogenesis.
- Heart disease is a common complication of diabetes, negatively impacting patient outcomes.
- Metformin, a type 2 diabetes drug, shows potential cardiac benefits in clinical studies.
Purpose of the Study:
- To investigate the effect of metformin on ERSS in primary rat cardiomyocytes.
- To determine which ERSS pathways are modulated by metformin.
- To clarify the role of CHOP in metformin-induced ER stress and cardiomyocyte apoptosis.
Main Methods:
- Primary rat cardiomyocytes were treated with metformin.
- Analysis of endoplasmic reticulum stress signaling pathways (PERK-ATF4, ATF6, IRE1-XBP1).
- Quantification of CHOP mRNA and protein expression; assessment of apoptosis.
Main Results:
- Metformin selectively activated the PERK-ATF4 pathway, not ATF6 or IRE1-XBP1.
- Significant upregulation of CHOP mRNA and protein was observed.
- Long-term CHOP induction by metformin did not lead to cardiomyocyte apoptosis.
Conclusions:
- Metformin induces distinct ER stress pathways in cardiomyocytes.
- CHOP is not necessarily a mediator of ER-stress-induced apoptosis.
- Metformin may offer cardioprotection via selective ERSS pathway activation in cardiomyocytes.
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