Author ORCID Identifier

0000-0001-5348-3008

Date of Award

5-1-2023

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Rafaela Feresin

Abstract

Approximately 650,000 new cases of heart failure (HF) are diagnosed annually with a 50% five-year mortality rate. HF is characterized by reduced left ventricular ejection fraction (EF) and hypertrophy of the left ventricular wall. The pathophysiological remodeling of the heart is mediated by increased oxidative stress and inflammation. Reactive oxygen species (ROS) derived from NADPH-oxidases (NOX), xanthine oxidase (XO), and mitochondria are the primary drivers of oxidative stress. In addition, damage associate molecular patterns (DAMPs) released from apoptotic cells can trigger toll-like receptor (TLR)4 activation, leading to an inflammatory response. Raspberries are rich in polyphenols which may favorably impact enzymes involved in redox homeostasis while also targeting inflammatory signaling. To elucidate these effects, Sprague Dawley rats consumed a 10% raspberry diet for seven weeks. At week three, HF was surgically induced via coronary artery ligation. Hemodynamics and morphology of the heart were assessed, and cardiac tissue was harvested at sacrifice from the rats following treatments. Expression of cardiac proteins involved in oxidative stress, inflammation, apoptosis and remodeling were assessed, and histological analysis was conducted. Additionally, human cardiomyocytes were pretreated with isolated raspberry polyphenol extract followed by CoCl2 treatment to chemically induce hypoxia. Redox status, apoptosis and mitochondrial dysfunction were assessed. Raspberries effectively preserve cardiac function and morphology, and this may be mediated by reduced TLR4 signaling. This coincided with reduced oxidative stress, apoptosis, and remodeling in vivo. In vitro, raspberry polyphenol extract attenuated CoCl2-induced oxidative stress and apoptosis in human cardiomyocytes despite pronounced hypoxia-inducible factor (HIF)-1α expression. In conclusion, these data indicate that the consumption of raspberries can reduce the underlying molecular drivers of HF, thus, leading to the observed improvements in cardiac functional capacity and morphology. This dietary strategy may be an effective alternative treatment in treating HF. However, further investigation in alternative models of HF are warranted.

DOI

https://doi.org/10.57709/35063691

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