Author ORCID Identifier
https://orcid.org/0000-0002-1873-1675
Date of Award
12-12-2022
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biology
First Advisor
Zhi-Ren Liu
Second Advisor
Ming-Hui Zou
Third Advisor
Hongyu Qiu
Fourth Advisor
Jenny Yang
Abstract
Substantial loss of cardiomyocytes during a heart attack and the onset of other cardiovascular diseases is the major cause of morbidity and mortality. Preservation of cardiomyocytes during cardiac injury would be the most effective strategy to manage these diseases in the clinic. However, there is no current effective treatment that can prevent cardiomyocyte loss during ischemic injury. Here we reported that systemic administration of G415R preserves cardiomyocytes and reduces cardiac fibrosis during cardiac infarction. G415R preserves cardiomyocytes by protecting cardiomyocytes from apoptosis and promoting cardiomyocyte proliferation. Preservation of cardiomyocytes by G415R reduces cardiac fibrosis because of decreased activation of cardiac fibroblasts. Our experiments show that EcPKM2 (G415R) exerts its action by interacting with integrin αvβ3 on cardiomyocytes. EcPKM2 interacts with integrin αvβ3 on cardiomyocytes to activate the FAK-PI3K signaling axis. Activation of FAK-PI3K by G415R suppresses PTEN expression to consequently regulate cardiomyocyte apoptosis resistance and proliferation under hypoxia and oxidative stress conditions.
Our studies uncover an essential mechanism for organ fibrosis progression. More importantly, we found that upregulation of endogenous PKM2 in cardiomyocytes in response to ischemic injury is very limited in the adult heart and is insufficient to preserve cardiomyocytes. Here we show that systemic injection of rPKM2 preserves cardiac function and promotes cardiac regeneration. Our discovery not only provides a new perspective for understanding the cardiac regeneration mechanism but also implies a potential target for clinical practice in cardiovascular disease.
DOI
https://doi.org/10.57709/32630517
Recommended Citation
Huang, Yang, "Systemic Administration of PKM2 Preserves Cardiomyocytes and Reduces Cardiac Fibrosis During Myocardial Infarction." Dissertation, Georgia State University, 2022.
doi: https://doi.org/10.57709/32630517
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