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Defining the role of Cytochrome b5 Reductase 3 in cardiomyocyte function

Carew, Nolan (2019) Defining the role of Cytochrome b5 Reductase 3 in cardiomyocyte function. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Sudden cardiac death in patients with heart failure is allied to an imbalance in reduction-oxidation (redox) signaling in cardiomyocytes. However, the basic pathways and mechanisms that preserve and afford cardiac resilience against stress are not fully understood. Using a combination of pharmacological, genetic and molecular in vivo mouse studies, and human translational studies, we show that cytochrome b5 reductase 3 (CYB5R3), an enzyme known to modulate redox signaling in erythrocytes and vascular cells, is essential for cardiac function through its ability to govern redox equilibrium. We provide evidence showing that diminished activity or restricted deletion of CYB5R3 in mouse adult cardiomyocytes causes increased oxidative stress, decreased coenzyme Q levels and heme iron oxidation. As a consequence of this redox imbalance, we find that CYB5R3 knockout mice is lethal due to sudden cardiac death associated with calcium mishandling, increased oxidative stress, decreased ATP production, and loss of hemoprotein redox regulation. Of clinical importance, we identify the high frequency CYB5R3 T150S variant that is enriched in African-Americans reduces CYB5R3 function in vitro. Additionally, a meta-analysis of African American CYB5R3 T150S carriers with heart failure and reduced ejection fraction showed accelerated mortality. Our combined findings underscore the importance of CYB5R3 in cardiomyocyte redox homeostasis and function, identifying CYB5R3 T150S as a potential disease modifying variant and biomarker in African-Americans. Importantly, these studies may help direct redox-based precision therapy for African-Americans who suffer from heart failure and are at risk of sudden cardiac death.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Carew, Nolanntc8@pitt.eduntc80000-0002-6995-6823
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPAGANO, PATRICKPAGANO@PITT.EDUPAGANO
Committee MemberSHIVA, SRUTISSS43@PITT.EDUSSS43
Committee MemberSTRAUB, ADAMASTRAUB@PITT.EDUASTRAUB
Thesis AdvisorSTRAUB, ADAMASTRAUB@PITT.EDUASTRAUB
Date: 2 October 2019
Date Type: Publication
Defense Date: 25 July 2019
Approval Date: 2 October 2019
Submission Date: 12 August 2019
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 55
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: BS - Bachelor of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: cytochrome b5 reductase 3, redox, heme-iron, myoglobin, CoQ, ubiquinone, heart, cardiomyocyte, sudden cardiac death
Date Deposited: 02 Oct 2019 16:52
Last Modified: 02 Oct 2019 16:52
URI: http://d-scholarship.pitt.edu/id/eprint/37361

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