DOI
https://doi.org/10.25772/YDXV-PW84
Defense Date
2022
Document Type
Thesis
Degree Name
Master of Science
Department
Physiology and Biophysics
First Advisor
Dr. Stefano Toldo
Abstract
The prevalence of heart failure (HF) has increased over the years and remains high. Although the incidence of HF is thought to no longer increase, the mortality rate and hospitalizations associated with HF remain high. Due to HF being an endpoint for many cardiovascular diseases and stemming from a variety of risk factors and comorbidities, there have been continued efforts to provide various effective treatments for HF patients. Even though both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) make up similar percentages of HF cases, there are currently several treatments approved for HFrEF but only a few approved for HFpEF. HFrEF is characterized by a reduced systolic and diastolic function, and HFpEF is mainly characterized by diastolic dysfunction. Angiotensin II (AngII) is elevated in virtually all HF patients, including HFpEF. It leads to hypertension, cardiac hypertrophy, fibrosis, and diastolic dysfunction. AngII induces a pro-inflammatory response independent from hypertension. IL-18 is a pro-inflammatory cytokine regulated by AngII, and causes the activation of many immune cells, including T helper 1 lymphocytes (Th1). Considering the literature connecting the effects of AngII and IL-18 on Th1 cells, together with data generated in my laboratory, we hypothesized that AngII activates Th1 cells to mediate diastolic dysfunction in an animal model of HFpEF.
By utilizing osmotic pumps delivering a subpressor dose of AngII in WT or TCR--/- mice, we found that the absence of mature T cells in TCR--/- mice protects from developing diastolic dysfunction. In addition, the adoptive transfer of WT Th1 cells into the TCR--/- mice re-induces diastolic dysfunction in TCR--/- mice. These findings suggest that AngII signaling, independent of hypertension, promotes Th1 cell-mediated diastolic dysfunction. The results of this study provide information that may help guide future experiments on determining how Th1 cells contribute to HFpEF and possible new therapies.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-3-2022