Date on Master's Thesis/Doctoral Dissertation
8-2024
Document Type
Doctoral Dissertation
Degree Name
Ph. D.
Department
Physiology and Biophysics
Degree Program
Physiology and Biophysics, PhD
Committee Chair
Tyagi, Suresh C.
Committee Member
Singh, Mahavir
Committee Member
Joshua, Irving G.
Committee Member
Sen, Utpal
Committee Member
Williams, Kim A.
Author's Keywords
MMP; chronic volume overload; ejection fraction; heart failure
Abstract
Heart failure is a prevalent cause of hospitalization globally, especially among older adults. The ejection fraction is a critical parameter in assessing and managing heart failure patients. As we age, the cardiovascular system undergoes changes that increase the risk of cardiovascular morbidity and mortality. One of the most significant structural features that occur with age is reduced or impaired contractility of the left ventricular wall of the heart. Matrix metalloproteinases (MMPs) play a crucial role in tissue remodeling, and their latency is linked with nitric oxide (NO). In the context of heart failure and constant stress, tissue remodeling leads to neurohormonal and cellular changes that impair cardiac function and decrease ejection fraction. Over the coming decades, as the number of heart failure patients continues to increase, more people are expected to have this heart failure with reduced ejection fraction. The increased activity of MMPs has been associated with several disease processes and is known to be involved in the pathogenesis of cardiovascular diseases. MMP-9 has been shown to control fibrosis and inflammation-related pathological remodeling in cardiovascular disease. This dissertation investigated the role of MMP-9 gene ablation in preserving ejection fraction during heart failure induced by the Arteriovenous fistula (AVF) model of volume overload. The study hypothesizes that MMP-9 gene ablation can prevent the transition to reduced ejection fraction in heart failure. To test the hypothesis, we created a chronic volume overload in mice using a 25-gauge needle to create an arteriovenous fistula (AVF) between the abdominal aorta and inferior vena cava approximately 0.5 cm below the left kidney. The mice were divided into four groups: i) wild type (WT) sham, ii) WT-AVF, iii) MMP9KO-sham, and iv) MMP9KO-AVF. The "in-gel" zymography technique was used to assess the quantitation of the proteolytic activity on substrate gels. Western blotting was used to assess protein expression levels in heart tissues. The multi-organ injury was assessed using tissue-specific creatine kinase isoforms, and cardiac function-related datasets were collected using an ultrasound procedure and myobath. The results of the study indicated that MMP-9 gene ablation could help preserve ejection fraction during heart failure by enhancing and preserving (a) cardiac signaling, (b) mitigating multi-organ injury, (c) mitigating dysregulated mitophagy and (d) mitigating endocardial endothelial myocyte coupling impairment.
Recommended Citation
Akinterinwa, Oluwaseun Ebenezer, "The role of matrix metalloproteinase-9 gene ablation in preserving ejection fraction during chronic volume overload-induced heart failure." (2024). Electronic Theses and Dissertations. Paper 4424.
Retrieved from https://ir.library.louisville.edu/etd/4424
