ORCID

http://orcid.org/0000-0001-6359-1416

Date of Award

Spring 5-15-2023

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Biochemistry)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Heart failure is the leading cause of death in the United States and current therapeutic interventions fail to reverse the disease progression. In the failing heart, pathological cardiac remodeling leads to disease progression: a process characterized by hypertrophy, inflammation, fibrosis, and metabolic remodeling. By pharmacologically targeting the nuclear hormone receptors estrogen receptor-related receptor α and γ (ERRα and γ), it may be possible to reverse the array of metabolic pathways that are pathologically inhibited in the failing heart. Fatty acids are the primary fuel source of the adult heart that generate the ATP required for each contraction; however, in heart failure there is a shift in fuel utilization to anaerobic glycolysis. This leads to inefficient ATP production and exacerbates the progression of the failing heart. Genetic loss of function of either ERRα or γ leads to development of heart failure in mice due to a shift in fuel preference from fatty acids to glucose, which is reminiscent of the alterations observed in patients with heart failure. We have identified and characterized novel ERR agonists that can be used as pharmacological tools to examine the potential beneficial effects of targeting the receptors to treat heart failure. Examination of gene expression changes induced by ERR agonists via RNA-sequencing in neonatal rat ventricular myocytes (NRVMs) revealed activation of many genes encoding enzymes in pathways such as tricarboxylic acid (TCA) cycle, fatty acid oxidation (FAO), oxidative phosphorylation (OXPHOS), and autophagy/mitophagy. We observed an increase in electron transport chair (ETC) proteins, mitochondrial content, activity, and respiration capacity with treatment of our novel ERR agonists. Additionally, a novel role for ERR in the autophagy-lysosome pathway was elucidated. Autophagy is the cells degradative and recycling pathway that is essential for physiological cardiac function and is dysregulated in the failing heart. NRVMs treated with ERR agonists show an increase in autophagic flux measured by markers such as the LC3 and p62 proteins. Importantly, the ERR agonist directly increases the expression of the transcription factor EB (TFEB), a master regulator of the autophagy-lysosome pathway. Upon ERR activation, we observed increased expression of TFEB target genes, highlighting the signaling cascade that leads to autophagy induction through ERR. In conclusion, targeting ERR is a promising potential therapeutic for improving heart function by both alleviating mitochondrial dysfunction and normalizing the deficit in autophagy that occurs in the failing heart.

Language

English (en)

Chair and Committee

Brian Finck Thomas Burris

Committee Members

James Janetka, Nicholas Davidson, Abhinav Diwan, Amber Stratman,

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