Doctor of Philosophy (PhD), Ohio University, 2018, Chemistry and Biochemistry (Arts and Sciences)

Advancing age is the primary risk factor for cardiovascular, cerebrovascular and renal diseases. The imbalance between prooxidative and antioxidative processes increase with senescence. The decrease in cytoprotective nitric oxide (NO) and increase in reactive oxygen species (ROS) such as superoxide (O2¯) and peroxynitrite (ONOO¯) are suggested to be the main factors of endothelial dysfunction and aging. Endothelial dysfunction is associated with the impaired generation of NO and overproduction of O2¯ resulting in the formation of cytotoxic ONOO¯. Replicative senescence of human endothelial cells (ECs) was analyzed here using human umbilical vein endothelial cells (HUVECs). In this study, we employed a nanomedical system to measure the concentration of NO, O2¯, and ONOO¯ simultaneously. Peroxynitrite is a powerful cytotoxic oxidant formed from the reaction between NO and O2¯. Nanosensors were placed near the endothelium and calcium ionophore-stimulated NO, O2¯, and ONOO¯ were measured. The present work was performed to investigate endothelial nitric oxide synthase (eNOS) dysfunction during aging of endothelial cells. The age-related cardiovascular diseases such as heart failure, atherosclerosis, ischemic heart disease and myocardial infarction can be associated with endothelial dysfunction. The nanomedical approach enabled us to characterize changes in eNOS coupling/uncoupling as a function of biological aging. The release of NO and ONOO¯ was studied in different passages in ethnic groups (Caucasian Americans (CAs), African Americans (AAs) and Asian Americans (ASAs)). Our results suggest that HUVECs of AAs are more susceptible to endothelial dysfunction during aging. The shortening of relative telomere length in aging coincided with a decrease of NO and increase of ONOO¯ concentrations. The imbalance between [NO] and [ONOO¯] was due to endothelial dysfunction. The treatment of aging endothelium with factors affecting the eNOS pathway (e.g., VAS2870, PEG-SOD, and L-ar (open full item for complete abstract)

Committee: Tadeusz Malinski PhD (Advisor) Subjects: Aging; Alternative Medicine; Cellular Biology; Chemistry; Developmental Biology; Endocrinology; Environmental Science; Environmental Studies; Epidemiology; Health Care; Health Sciences; Immunology; Medicine; Microbiology; Molecular Biology; Molecular Chemistry; Molecules; Nanoscience; Nanotechnology; Neurobiology; Neurology; Neurosciences; Oncology; Organic Chemistry; Organismal Biology; Pharmaceuticals; Pharmacology; Pharmacy Sciences; Physiology; Polymer Chemistry; Sports Medicine; Therapy; Toxicology; Zoology