Dissertation
Investigating SQOR-catalyzed H₂S metabolism and its therapeutic potential in heart failure
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2020
DOI:
https://doi.org/10.17918/00000315
Abstract
Hydrogen sulfide (H₂S) belongs to a family of endogenously synthesized gasotransmitters, in which H₂S is the only member enzymatically degraded. In the heart, H₂S is mainly synthesized by cystathionine-gamma-lyase and regulated by the mitochondrial membrane enzyme, sulfide:quinone oxidoreductase (SQOR). SQOR catalyzes the first irreversible step in the 2-electron oxidation of H₂S to sulfane sulfur (S0). Two additional substrates, coenzyme Q (CoQ) and S0 acceptor, are required by the SQOR reaction. After the S0 metabolite is released, a final electron transfer from SQOR-bound FAD reduces CoQ and completes catalysis. There are two proposed pathways for H₂S metabolism, which differ in the S0 acceptor used. We propose that sulfite is the major physiological S0 acceptor in the heart and the liver based on measured tissue concentrations of sulfite and alternate acceptors, steady-state kinetics, and simulated SQOR reactions. H₂S signaling has been previously reported to activate cardioprotective mechanisms in experimental models of heart failure with reduced ejection fraction (HFrEF). HFrEF patients exhibit reduced H₂S levels. Our lab identified a novel and potent small-molecule inhibitor of SQOR, STI1, designed to increase H₂S levels by slowing its mitochondrial metabolism. We investigated the cardioprotective effect of STI1 and showed it reduces cardiomyocyte hypertrophy in cell-based assays. We further assessed STI1 in murine model of aortic stenosis, which induces hypertrophy and HFrEF. We demonstrated that STI1 prevented systolic dysfunction and progression into HFrEF that is attributed to the reduction of maladaptive remodeling. This proof-of-concept study demonstrates that SQOR inhibition is a viable cardiotherapeutic target for HFrEF treatment.
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Details
- Title
- Investigating SQOR-catalyzed H₂S metabolism and its therapeutic potential in heart failure
- Creators
- Kristie Dawn Cox
- Contributors
- Marilyn S. Jorns (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 167 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014833045904721