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Pluripotent Stem Cell Derived Cardiac Cells for Myocardial Repair
Published on: February 3, 2017
Extracellular PKM2 Preserves Cardiomyocytes and Reduces Cardiac Fibrosis During Myocardial Infarction
Yang Huang1, Bin Li1, Zongxiang Gui2
1Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Insights
A novel PKM2 mutant (G415R) preserves heart cells after heart attacks by preventing death and promoting proliferation. This extracellular PKM2 therapy also reduces cardiac fibrosis, offering a potential new treatment for cardiovascular diseases.
Area of Science:
- Cardiovascular Research
- Cellular Biology
- Biochemistry
Background:
- Cardiovascular diseases cause significant mortality due to cardiomyocyte loss.
- Current treatments lack effective strategies to prevent cardiomyocyte death during cardiac injury.
- Identifying mechanisms for cardiomyocyte preservation is crucial for managing heart conditions.
Purpose of the Study:
- To investigate the therapeutic potential of a recombinant PKM2 mutant (G415R) in preserving cardiomyocytes during myocardial infarction.
- To elucidate the protective mechanisms of extracellular PKM2 (EcPKM2) in cardiac injury.
- To explore EcPKM2 (G415R) as a potential therapeutic target for heart attack treatment.
Main Methods:
- Systemic administration of recombinant PKM2 mutant (G415R) in a myocardial infarction model.
- Assessment of cardiomyocyte survival, proliferation, and cardiac fibrosis.
- Investigation of EcPKM2 (G415R) interaction with cell surface receptors, specifically integrin αvβ3.
- Analysis of downstream signaling pathways including FAK, PI3K, and PTEN.
Main Results:
- Systemic G415R administration preserved cardiomyocytes and reduced cardiac fibrosis post-myocardial infarction.
- EcPKM2 (G415R) protected cardiomyocytes from apoptosis and promoted proliferation.
- EcPKM2 (G415R) reduced cardiac fibroblast activation, contributing to decreased fibrosis.
- EcPKM2 (G415R) interacted with integrin αvβ3, activating the FAK-PI3K pathway and suppressing PTEN.
Conclusions:
- Extracellular PKM2 (G415R) demonstrates significant cardioprotective effects by preserving cardiomyocytes and reducing fibrosis.
- The mechanism involves integrin αvβ3-mediated activation of the FAK-PI3K/PTEN axis, enhancing resistance to apoptosis and promoting proliferation.
- EcPKM2 (G415R) represents a promising therapeutic strategy for treating heart attacks and other cardiovascular diseases.
Abstract:
Substantial loss of cardiomyocytes during heart attacks and onset of other cardiovascular diseases is a major cause of mortality. Preservation of cardiomyocytes during cardiac injury would be the most effective strategy to manage these diseases in clinic. However, there is no effective treatment strategy that is able to prevent cardiomyocyte loss. We demonstrate here that the systemic administration of a recombinant PKM2 mutant (G415R) preserves cardiomyocytes and reduces cardiac fibrosis during myocardial infarction. G415R preserves cardiomyocytes by protecting the cardiomyocytes from dying and by promoting cardiomyocyte proliferation. Preservation of cardiomyocytes by extracellular PKM2 (EcPKM2) reduces cardiac fibrosis because of the decreased activation of cardiac fibroblasts. Our experiments show that EcPKM2 (G415R) exerts its action by interacting with integrin avb3 on cardiomyocytes. EcPKM2(G415R) activates the integrin-FAK-PI3K signaling axis, which subsequently suppresses PTEN expression and consequently regulates cardiomyocyte apoptosis resistance and proliferation under hypoxia and oxidative stress conditions. Our studies uncover an important cardiomyocyte protection mechanism. More importantly, the activity/action of EcPKM2 (G415R) in preserving cardiomyocyte suggesting a possible therapeutic strategy and target for the treatment of heart attacks and other cardiovascular diseases.
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