Author ORCID Identifier
Date Available
2-28-2023
Year of Publication
2023
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Nutritional Sciences
First Advisor
Dr. Alan Daugherty
Abstract
Abdominal aortic aneurysms (AAAs) are permanent luminal dilations of the vessel wall that can result in rupture and death. There is currently no evidence-based treatment to prevent or attenuate the development of this devastating condition. Although vascular inflammation is known to be one of the hallmarks of AAA, underlying mechanisms that initiate inflammatory pathways in the aorta are not clearly known. High-mobility group box 1 (HMGB1), a highly conserved nonhistone DNA-binding nuclear protein, may contribute to vascular diseases. Since whole-body genetic deletion of HMGB1 is embryonic lethal, pharmacological approaches have been used to manipulate HMGB1 in mice. However, it remains desirable to genetically manipulate HMGB1 to further understand its role. In the body of work presented here, we assessed the contributing role of HMGB1 in AAA development and the efficacy of neutralization and a novel antisense oligonucleotides (ASOs) approach to deplete HMGB1 in mice.
To examine the role of HMGB1 in AAA development, we assessed the gene expression profile of human and murine aneurysmal samples, indicating a marked upregulation of inflammatory pathways and HMGB1 in the abdominal aorta of diseased tissue. Further validations at the early stages of experimental AAA by utilizing the Angiotensin II (AngII) model also indicated a marked increase of HMGB1 protein abundance in the abdominal aorta of male LDLr-/- mice. To determine the role of HMGB1 inhibition in AngII-induced AAAs, a monoclonal anti-HMGB1 antibody (2G7) or an isotype-matched control were intraperitoneally injected into 8-10-week-old male LDLr-/- mice that were infused with AngII for 28 days. Neutralizing HMGB1 with a low dose did not show a significant decrease in the abdominal aortic diameter of AngII-infused mice. Next, we examined the efficacy of seven different ASOs in reducing HMGB1 protein abundance at selected intervals. Either ASOs or phosphate-buffered saline (PBS) were injected into male C57BL/6J mice (8-10-week-old) at days 0 and 3 in the initial week and then once a week during the remainder of the study. Subsequently, mRNA and protein abundance of HMGB1 were determined in the various tissues. After screening various ASOs to determine the most optimum version and to further investigate the role of systemic HMGB1 inhibition in aneurysm formation, hypercortisolemic male mice fed a Western diet were infused with AngII for four weeks to induce aneurysm and were injected with PBS or HMGB1 ASO. Our results indicated a profound significant attenuation of AAA in ASO administered group. Collectively, our data established that the ASO approach could significantly decrease HMGB1 expression, and its inhibition in an experimental aneurysm model can profoundly attenuate the AngII-induced AAA formation. Further, utilizing an ASO approach to inhibit HMGB1 can provide more clear insights into understanding the biological functions of HMGB1 with strong clinical significance.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.037
Recommended Citation
Mohammadmoradi, Shayan, "THE ROLE OF HIGH MOBILITY GROUP BOX-1 PATHOBIOLOGY IN ANGIOTENSIN II-INDUCED ABDOMINAL AORTIC ANEURYSMS" (2023). Theses and Dissertations--Pharmacology and Nutritional Sciences. 45.
https://uknowledge.uky.edu/pharmacol_etds/45
