Dissertation
Klotho-Sirt1-CHK2 pathways in the regulation of cardiac function in aging and post-myocardial injury
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Summer 2024
DOI: 10.25820/etd.007718
Abstract
Aging significantly impairs cardiac function and stem cell regenerative capacity, leading to heart failure with preserved ejection fraction (HFpEF) and impaired tissue homeostasis. We investigated the therapeutic potential of the anti-aging hormone α-Klotho (sKL) in ameliorating these age-related phenotypes through its modulation of the Sirtuin1 (Sirt1)-Checkpoint kinase 2 (CHK2) signaling pathway. Aged wild-type and heterozygous Klotho-deficient mice were treated daily with sKL for 10 weeks, and their cardiac function and cell proliferation across various tissues were comprehensively assessed.
Our results demonstrate that sKL supplementation not only reversed aging-related changes by enhancing proliferative markers and reducing DNA damage but also improved cardiac function by mitigating hypertrophy, diastolic dysfunction, and exercise intolerance. These findings propose sKL treatment as a promising intervention for combating HFpEF and improving tissue regeneration, highlighting its broad therapeutic implications in aging research.
We next sought to investigate the role of CHK2 in cardiomyocyte proliferation during development and post-myocardial infarction (MI). We employed cardiac-specific AAV9-CHK2shRNA treatments post-MI to investigate the effect of CHK2 suppression on cardiac function, scar size, and cardiomyocyte proliferation. We also utilized spatial transcriptomics to analyze differentially expressed genes across different cardiac regions and identify crucial gene programs modulated in a spatiotemporal manner post-MI.
We identified CHK2 as an important regulator of cell cycle arrest in vivo and in vitro. CHK2 and its active form, p-CHK2, expression significantly increase during development and post-MI. CHK2 suppression post-MI resulted in improved cardiac function, reduced scar size, and increased cardiomyocyte proliferation markers. Spatial transcriptomic analysis indicated that CHK2shRNA-treated hearts maintained a healthier cardiomyocyte population, with upregulation of genes promoting mitochondrial biogenesis and enhanced cardiac contractility. Moreover, changes in the expression of upstream transcriptional regulators suggest a shift from repressed metabolic states to an active state favorable to repair and adaptation.
Taken together, we identify CHK2 suppression as a crucial contributor in improving post-MI cardiac function and scar reduction, potentially by promoting endogenous cardiomyocyte proliferation. These findings highlight the multifaceted role of CHK2 beyond cell cycle regulation, implicating its suppression as a prospective strategy for cardiac repair.
Details
- Title: Subtitle
- Klotho-Sirt1-CHK2 pathways in the regulation of cardiac function in aging and post-myocardial injury
- Creators
- Nastaran Daneshgar
- Contributors
- Dao-Fu Dai (Advisor)Chad Grueter (Advisor)Bing Li (Committee Member)Jia Luo (Committee Member)Long-Sheng Song (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science
- Date degree season
- Summer 2024
- DOI
- 10.25820/etd.007718
- Publisher
- University of Iowa
- Number of pages
- xix, 130 pages
- Copyright
- Copyright 2024 Nastaran Daneshgar
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Date submitted
- 07/16/2024
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 116-129).
- Public Abstract (ETD)
- As we age, our hearts often struggle to pump blood as effectively as they once did, and our body’s ability to repair damaged tissues diminishes. This can lead to a condition called heart failure, where the heart muscle becomes stiff and unable to fill properly with blood. Our research explores the use of a naturally occurring hormone called α-Klotho, which has shown promise in reversing age-related deterioration in the heart and other tissues. In our experiments, we treated aged mice, both normal and those genetically modified to produce less α-Klotho, with daily doses of this hormone. After ten weeks of treatment, we assessed their heart function and the ability of their tissues to regenerate. The results showed the hormone treatment improved heart function. Additionally, we studied a specific protein, checkpoint kinase 2 (CHK2), that helps regulate the cell’s response to DNA damage and controls cell division. Suppressing this protein after a heart attack led to improved heart function and less scarring. This suggests that managing CHK2 expression could be a new way to help the heart heal after injury. In summary, our study highlights the potential of α-Klotho treatment and CHK2 management as new strategies to combat heart aging and improve recovery from heart injuries, offering hope for better heart health in our later years.
- Academic Unit
- Carver College of Medicine
- Record Identifier
- 9984698054002771
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