Dissertation
THE PHYSIOLOGICAL AND PATHOLOGICAL ROLES OF PKA REGULATORY SUBUNIT 1α IN THE HEART
Washington State University
Doctor of Philosophy (PhD), Washington State University
01/2021
DOI:
https://doi.org/10.7273/000006445
Handle:
https://hdl.handle.net/2376/120501
Abstract
Protein kinase A (PKA) activity is pivotal for proper functioning of the human heart, and its dysregulation has been implicated in a variety of cardiac pathologies. PKA regulatory subunit 1α (R1α, encoded by the PRKAR1A gene) is highly expressed in the heart, and controls PKA kinase activity. However, the role of PRKAR1A in heart development and disease remains largely unknown. Patients with PRKAR1A mutations are often diagnosed with Carney complex (CNC) in early adulthood and may die from heart failure later in life. Here, we showed that left ventricular mass was reduced in young CNC patients. Cardiac-specific heterozygous ablation of Prkar1a in mice reduced heart weight and cardiomyocyte size through inhibiting Drp1-mediated mitochondrial fission.
Myocardial infarction (MI) causes high mortality in the United States. Reperfusion therapy, the most effective treatment for MI, paradoxically provokes ischemia/reperfusion (I/R) injury characterized by rapid, irreversible loss of cardiomyocytes through necrosis. Our recent genome-wide RNAi screen identifies PRKAR1A as a potential necrosis suppressor gene. Here we showed that Prkar1a deficiency represses the p62-Keap1-Nrf2 axis and impairs the antioxidant defense system, leading to aggravated oxidative stress, necrotic cell death and myocardial damage following I/R.
In conclusion, Prkar1a deficiency impedes postnatal heart growth, augmented cardiomyocyte necrosis and exaggerated myocardial I/R injury. Our findings uncover a novel role of PKA in oxidative stress and necrosis. Therefore, PKA may serve as a potential drug target for preventing reperfusion injury and improving clinical outcomes of MI.
Metrics
1 File views/ downloads
33 Record Views
Details
- Title
- THE PHYSIOLOGICAL AND PATHOLOGICAL ROLES OF PKA REGULATORY SUBUNIT 1α IN THE HEART
- Creators
- Yuening Liu
- Contributors
- Zhaokang Cheng (Advisor)Susan Marsh (Committee Member)Salah-Uddin Ahmed (Committee Member)Weimin Li (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Pharmacy and Pharmaceutical Sciences, College of
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 146
- Identifiers
- 99900599557401842
- Language
- English
- Resource Type
- Dissertation