DOI
https://doi.org/10.25772/GFKX-1133
Defense Date
2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Physiology and Biophysics
First Advisor
Stefano Toldo
Second Advisor
Antonio Abbate
Third Advisor
Fadi Salloum
Fourth Advisor
Clive Baumgarten
Fifth Advisor
Rebecca Martin
Abstract
Background: Heart failure (HF) is a clinical syndrome caused by impaired cardiac function accompanied by symptoms of dyspnea, fatigue, congestion, and exercise intolerance. HF remains a leading cause of hospitalization and mortality in the United States and worldwide, and its prevalence continues to increase. A chronic and low-grade state of inflammation is a key factor in the pathophysiology of HF development and acute decompensation in patients with HF. Interleukin-1 is a prototypal, pro-inflammatory cytokine implicated in HF and as a reversible negative modulator of cardiac contractility. In healthy adult mice, administering a single dose of recombinant-mouse IL-1β (IL-1β) precipitates acute systolic dysfunction. The systolic dysfunction peaks 4 hours after administration and resolves after 24 hours. The transient nature of IL-1-induced cardiac dysfunction is noteworthy for HF treatment. Nonetheless, the blockade of IL-1, as with many other immunomodulatory treatment approaches, may increase the risk of infection and infection-related complications and inadvertently block the protective effects of IL-1-mediated inflammation. Therefore, understanding the mechanism of IL-1 induced cardiac dysfunction may uncover promising targeted therapeutics for the treatment of HF, while avoiding the negative effects of whole IL-1 blockade, with the goal of increasing quality of life as well as decreasing cardiovascular and all-cause mortality in HF patients. Phosphoinositide 3-kinase gamma (PI3K p110γ) has been implicated in myocardial contractile depression through the involvement of phosphodiesterase 3 (PDE3), and a novel unconventional IL-1 receptor signaling pathway through PI3K p110γ has been described in inflammation and cancer. Whether the cardiac modulatory effects of IL-1 are mediated through PI3K p110γ is not known. Furthermore, IL-1 is increased in acute myocardial infarction and HF, and has been shown to promote adverse remodeling in both. Blockade of IL-1 has shown promise in several clinical trials as safe and with the potential to decrease hospitalization and improve exercise performance in HF patients. However, the direct role of IL-1 on exercise tolerance is unknown, and the effect of IL-1 blockade on exercise tolerance in acute myocardial infarction and ischemic HF has not been studied in preclinical models. Likewise, IL-1 activity is implicated in aging-associated inflammation (inflamm-aging), and IL-1 may be a modulator of metabolic and structural changes causing aging-associated cardiomyopathy. Herein, we conducted three major studies in murine models to further understand IL-1 mediated cardiac effects. 1.) We tested whether IL-1 signaling,in vitro and in vivo, is mediated through the PI3K p110γ serine/threonine protein kinase scaffolding function linked to PDE3 in an effort to elucidate the mechanism by which IL-1 induces cardio-depression in the mouse. 2.) In a translational relevant study, we evaluated the effect of IL-1 blockade with Anakinra, a human recombinant IL-1 receptor antagonist (IL-1Ra), on exercise tolerance in non-reperfused acute myocardial infarction (AMI), as well as in a model of HF in the mouse. 3.) Using a murine model of genetically knocked out IL-1 receptor I (IL-1RI), the receptor through which IL-1 signals, we assessed the role of IL-1 in aging-associated cardiomyopathy. Results: IL-1 induces both PI3K p110γ mRNA and protein in IL-1 treated in vivo murine whole heart tissue and in IL-1 treated murine primary cardiomyocytes in culture. The lack of PI3K p110γ (p110γKO) confers resistance to IL-1-induced systolic dysfunction, although this was not true in mice who had catalytically inactive/kinase dead PI3K p110γ (p110γΚD). The administration of Milrinone (PDE3 inhibitor) fully restored systolic function in the setting of IL-1-induced systolic dysfunction. In addition, the administration of IL-1β to mice promoted exercise intolerance. The blockade of IL-1 with Anakinra counteracted exercise intolerance after non-reperfused acute myocardial infarction (AMI) in mice. Anakinra also rescued cardiac contractile reserve and exercise tolerance in a murine model of ischemic HF. Finally, the deletion of IL-1 receptor type I (IL-1RIKO) in mice prevented the development of aging-associated cardiomyopathy and HF phenotype in aging mice by preventing aging-associated left ventricular hypertrophy, diastolic dysfunction, and the increase in end-diastolic pressure and myocardial interstitial fibrosis. Conclusion: Our findings implicate IL-1 signaling as a key cardio-depressant in HF and the blockade of IL-1 or its downstream effectors hold promise for treating HF. Therefore, our results encourage further study of IL-1 in heart failure.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
3-13-2023
Included in
Biochemistry Commons, Cardiovascular Diseases Commons, Cellular and Molecular Physiology Commons, Immune System Diseases Commons, Molecular Biology Commons, Nutritional and Metabolic Diseases Commons