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Thesis
Dual loss of RGS2 and RGS5 decreases cardiomyocyte contractility and causes arrhythmia in adult mice
Master of Science (M.S.), Drexel University
2018
DOI:
https://doi.org/10.17918/D8XH4G
Abstract
Cardiomyocyte contractility is essential to maintaining proper cardiac output and blood flow throughout the circulatory system. This action is dependent upon proper G protein-coupled receptor (GPCR) signaling. Previous studies showed G-protein dysregulation due to the loss of regulator of G protein signaling (RGS) 2 and 5, separately, impairs cardiac structure and function, including hypertrophy and arrhythmia. RGS2 and 5 are GTPase activating proteins (GAPs) that accelerate the hydrolysis of GTP by G proteins, resulting in a rapid signaling termination. We examined how the dual absence of Rgs2 and 5 (Rgs2/5 dbKO) affects cardiac function. We found that Rgs2/5 dbKO mice showed cardiac hypertrophy and a dilated left ventricle at baseline. Cardiac contractile response to a dobutamine stress test was sex-dependently reduced in male Rgs2/5 dbKO relative to WT mice. In addition, chronic systemic infusion of the [beta]-adrenergic receptor agonist, isoproterenol, led to marked exacerbation of cardiac hypertrophy in Rgs2/5 dbKO mice. When subjected to surgery-induced stress, male Rgs2/5 dbKO mice showed 80% mortality within 72 - 96 hours after surgery, accompanied by extreme hypertension and decreased cardiac contractile function. At the cellular level, cardiomyocytes from Rgs2/5 dbKO mice showed reduced contractile response to electrical pacing and exhibited irregular excitation-contraction coupling and death in response to increasing concentrations of different [beta]-adrenergic agonists. We conclude that RGS2 and 5 act synergistically within the heart to regulate signaling mechanisms that mediate cardiac structure and function. Thus, a thorough understanding of the G protein signaling regulation by multiple RGS proteins is key to identifying novel therapeutic targets for heart disease.
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Details
- Title
- Dual loss of RGS2 and RGS5 decreases cardiomyocyte contractility and causes arrhythmia in adult mice
- Creators
- Tyler Francis Bernadyn - DU
- Contributors
- Patrick Osei-Owusu (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- vii, 42 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 8120; 991014632438304721