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Role of PI3Kα and PI3Kβ Signaling in Post-infarction Cardiac Remodeling

  • Author / Creator
    Chen, Xueyi
  • Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, while ischemic heart disease (IHD) dominates the cause of CVD mortality. Following myocardial infarction (MI), the heart experiences a series of structural and functional changes, termed post-infarction cardiac remodeling, characterized by ventricular dilation, eccentric hypertrophy, inflammation, and fibrotic scar formation. Within the heart, cardiomyocytes and endothelial cells are critical to maintain cardiac function. Moreover, they are essential players in orchestrating the complex post-infarction responses. Cardiomyocytes, especially those in the infarcted region, struggle to survive, while the survived cardiomyocytes undergo hypertrophy attempting to maintain cardiac function. Cardiac endothelial cells can be rapidly activated and undergo angiogenesis in response to myocardial injury, orchestrating cardiac remodeling processes. Attempting to attenuate post-MI adverse remodeling, I evaluated the roles of PI3K isoforms in IHD. Class I phosphoinositide 3-kinases (PI3K) are conserved lipid kinases that produce the second massager PIP3 which subsequently leads to the activation of various downstream effectors. They contain four isoforms, PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. While PI3Kα and PI3Kβ are ubiquitously expressed, PI3Kδ and PI3Kγ are enriched in leukocytes. Previous research has highlighted the pro-survival roles of PI3Kα in tumor progression, leading to the development of PI3Kα inhibitors as a novel anti-cancer therapy. In the heart, PI3Kα is involved in cardiomyocyte hypertrophy, contractility, and post-injury viability. Moreover, PI3Kα in the endothelial cells participates in angiogenic processes. On the contrary, PI3Kβ has been considered to be redundant for decades. Recent studies have suggested the function of PI3Kβ in cell survival, DNA replication, and DNA repair. Nonetheless, little is known about the role of PI3Kα and PI3Kβ in post-MI cardiac remodeling. With the knowledge gaps in mind, I investigated how PI3Kα and PI3Kβ function in endothelial cells and cardiomyocytes to modulate cardiac function and post-infarct ventricular remodeling. First, I investigated whether PI3Kα inhibition affects cardiac health and post-MI cardiac healing and remodeling. WT mice with daily and oral PI3Kα inhibitor-BYL719 administration for 10 days showed reduced left ventricular longitudinal strain with normal ejection fraction, weight loss, decreased heart weight, body composition alteration, and prolonged QT interval. BYL719 also aggravated cardiac dysfunction and cardiac remodeling after MI, with increased apoptosis, elevated inflammation, decreased vascular density, and inhibited Akt/GSK3β/eNOS signaling. Genetic inactivation of PI3Kα specifically in cardiomyocytes suggests PI3Kα regulates baseline cardiac function. Either endothelial- or cardiomyocyte-PI3Kα inactivation led to a markedly deterioration of cardiac function after MI. Whilst lack of endothelial PI3Kα suppressed endothelial repair with decreased endothelial survival, proliferation, and vascular density, loss of cardiomyocyte PI3Kα enhanced post-MI cell apoptosis and inhibited hypertrophy. BYL719 suppressed endothelial Akt/eNOS activation, cell viability, proliferation, and angiogenic responses. Moreover, it decreased hypoxia associated Akt activation and cell survival in isolated adult mouse cardiomyocytes. Thus, PI3Kα inhibition is detrimental to post-MI cardiac repair by suppressing endothelial repair, cardiomyocyte survival, and hypertrophic responses. I then examined the role of endothelial and cardiomyocyte PI3Kβ in post-infarct cardiac remodeling. Loss of endothelial PI3Kβ resulted in marked resistance to infarction with decreased mortality, improved systolic function, preserved microvasculature, and enhanced Akt activation. Cultured endothelial cells with PI3Kβ knockout or inhibition displayed preferential PI3Kα/Akt/eNOS signaling that consequently promoted angiogenesis. In contrast, mice with cardiomyocyte PI3Kβ-deficiency exhibited adverse post-infarct ventricular remodeling with larger infarct size and deteriorated cardiac function, which was due to enhanced susceptibility of cardiomyocytes to ischemia-mediated cell death. Disruption of cardiomyocyte PI3Kβ signaling compromised nuclear PI3Kβ and phospho-Akt levels, leading to perturbed gene expression and elevated pro-cell death protein levels. This study demonstrates novel, differential, and cell-specific functions of PI3Kβ in the ischemic heart. While the loss of endothelial PI3Kβ activity is cardioprotective, cardiomyocyte PI3Kβ is required for myocardial ischemic recovery. In summary, the studies have demonstrated the cell type-specific function of PI3Kα and PI3Kβ in cardiac tissue in the healthy and ischemic heart. Manipulation of PI3Kα and/or PI3Kβ has therapeutic potential in IHD. While amplification of cardiac PI3Kα might provide beneficial effects to the ischemic heart by protecting cardiomyocyte from apoptosis and supporting angiogenesis, small-molecule inhibitors targeting PI3Kβ might improve post-MI cardiac repair by enhancing vascular repair. Moreover, with the growing evidence supporting the use of PI3Kα inhibitors in advanced tumors, the concerns of potential cardiotoxicity of chronic treatments should be raised, especially when coinciding with an ischemic event.

  • Subjects / Keywords
  • Graduation date
    Spring 2020
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/r3-aees-9307
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.