Author ORCID Identifier
Date Available
5-10-2025
Year of Publication
2023
Degree Name
Doctor of Philosophy (PhD)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Nutritional Sciences
First Advisor
Dr. Xiangan Li
Abstract
Unexplained sudden death continues to be a major public health crisis as AHA reports that 1,000 people suffer sudden cardiac arrest each day in the U.S. with only 10% surviving. A number of ongoing challenges hinder to understand the sudden death. Thus, investigating underlined mechanisms of sudden death is urgent. Unexpectedly, I found a high cholesterol diet (HCD)-induced sudden death preclinical model. Although HCD is associated with a higher risk of cardiovascular disease (CVD) and the subendothelial lipoprotein retention theory is well established for atherosclerosis development, these theories cannot explain the sudden death in my model because atherosclerosis and CVD require a long time to develop. Scavenger receptor class B type I (SR-BI), a high-density lipoprotein (HDL) receptor, has important role in reverse cholesterol transport (RCT). We found that HCD induces hemolysis with impaired RCT, which causes multiple organ injuries and sudden death. We sought to elucidate the downstream mechanism after hemolysis. Finally, NLRP3 inflammasome inhibitors showed promising protection against HCD-induced sudden death. We also identified SR-BI as a heme scavenger receptor, which protects against hemolysis- and heme-induced lethality. Taken together, we identified 1) HCD induces sudden death via hemolysis. 2) SR-BI mediates heme uptake, which protects against heme- and hemolysis- induced death. This project is innovative because this study will identify a new mechanism of HCD-induced sudden death to deepen understanding of unexpected sudden death.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2023.215
Funding Information
NIH R01GM121796 and NIH 1R35GM141478 (X-A Li)
Recommended Citation
Ito, Misa, "HIGH CHOLESTEROL DIET INDUCES SUDDEN DEATH IN MICE WITH IMPAIRED REVERSE CHOLESTEROL TRANSPORT" (2023). Theses and Dissertations--Pharmacology and Nutritional Sciences. 48.
https://uknowledge.uky.edu/pharmacol_etds/48
