Hypertension is a complex multifactorial pathology that is a major risk factor for the development of cardiovascular disease, stroke, and end stage renal disease. In the United States, hypertension affects over 1 in 3 adults and comprises an annual cost of over $58 billion in the healthcare industry. While remarkable strides in the diagnosis and treatment of hypertension have been made since the pathology was first treated in the 1960s, a remarkable 13% of patients with elevated blood pressures are classified as resistant hypertensive, where blood pressure remains uncontrolled while on three or more classes of anti-hypertensive drugs. This treatment gap suggests that researchers need to develop and utilize translational models that recapitulate the pathologies seen in patient populations. Non-human primates (NHP) are highly similar to humans in terms of physiology, circadian rhythmicity, behavior, and gene sequence and structure. Development of NHP models that spontaneously develop pathologies, like spontaneous hypertension, provide novel and vital tools to studying disease. Overall, this dissertation is a comparative analysis of the mechanisms that drive the development of spontaneous hypertension in Chlorocebus aethiops sabaeus, an Old World non-human primate, and known mediators of essential hypertension in human populations. Chapter 2 presents how hypertensive (HT) African Green Monkeys (AGMs) are older, with elevated heart rates, increased renal vascular wall/lumen ratios, and altered glomerular morphologies compared to normotensive (NT) controls. Chapter 3 describes metabolic studies performed in a large cohort of animals that identified elevated proteinuria and ion excretion in HT AGMs compared to NT animals. Chapter 4 focuses on the contribution of sympathetic nervous system to the development of hypertension in this animal model and describes the significant left ventricular hypertrophy and elevation of adrenergic receptor mRNA in HT AGMs. Chapter 5 examines how age affects hypertension and renal function in the NT and HT AGMs. Together these data provide a foundational basis for the development of spontaneous hypertension in the AGM and provide a novel translational model for the study of cardiovascular disease.

Philosophiae Doctor - PhD / In this century most major medical advances have resulted in part from research on animals and non-human primates such as the African green monkey and therefore often serve as a critical link between basic research and human clinical application. Due to its close evolutionary relationship to humans, the African green monkey is known to be an excellent and most sought after models for studies of human cardiovascular disease (CVD). While the human genome project and some others related to model organisms are very well advanced or even complete, little sequence information has been acquired for the African green monkey. Given the importance of this species in biomedical research generally and CVD specifically, and the fundamental significance of sequence data, it is critical that this paucity of genome information concerning this specific animal model be addressed in order to better define the molecular basis and to further understand the mechanism of cholesterol metabolism in this species which will also contribute immensely to primatology. There is a growing interest in the role of genetic polymorphisms in predicting susceptibility to disease and responsiveness to drug interventions. Since plasma lipid abnormalities are risk factors for coronary atherosclerosis, determination of these plasma lipid concentrations, especially for genes involved in lipid transport and metabolism may be influenced by genetic variations. In this study, the African green monkey was used as a model to evaluate the effect of niacin on plasma lipids and reverse cholesterol transport by examine gene expression and the influence of several polymorphisms found in genes that are involved in cholesterol metabolism in humans. A survey of genetic variation spanning ten prioritised “candidate” genes was conducted, all of which are known to produce proteins that play key roles in the reverse cholesterol pathway (RCT), and in the homeostatic regulation of blood lipid profiles related to cardiovascular health and disease. everse transcription polymerase chain reaction (RT-PCR) was used to evaluate mRNA expression of those “candidate” genes. Twenty two coincident singlenucleotide polymorphisms (cSNPs), reported to play a vital role in RCT, were genotyped within these genes. This study’s findings implicate a subset of six of the twenty two genetic variants, spanning five “candidate” genes. To assess possible involvement of these prioritised “candidate” genes and their polymorphisms, biochemical analyses of known risk factors of coronary artery disease such as HDL-C and LDL-C were conducted. Eight healthy African green monkeys were entered in this study of which four were treated with niacin at an escalating dosage. Their mean lipid-lowering response following drug therapy was analysed, compared to those with the same genotype in a control group. Niacin treatment was associated with a considerable reduction in LDL-Cholesterol, up-regulation of HDL synthesis, and increase of apo A-1 levels. Gene expression had minimal effect on niacin treatment, except CYP7A1 which was down-regulated at the same time when considerable change in HDL-C, LDL-C and apoA-1 levels was observed. The presence of CYP7A1:Asn233Ser polymorphism may have played a critical role in metabolising niacin and influencing the up-regulation of HDL-C synthesis in the African green monkey. Although cholesterol lowering alone may explain the anti-atherosclerotic effect of niacin on HDL-C, in this study, gene expression data also shed some light in supporting the hypothesis that genetic variants may influence the expression of genes involved in RCT, which may also have played a role in the anti-atherosclerotic effect of the drug.

CYP2D6 metabolizes a range of centrally acting drugs, neurotoxins, and endogenous neurochemicals. Higher levels of brain, but not liver, CYP2D6 have been identified in alcoholics and smokers, suggesting exposure to ethanol and/or nicotine may induce brain CYP2D6. We investigated the independent and combined effects of chronic ethanol self-administration and nicotine treatment on CYP2D expression. METHODS: Monkeys were randomized into 4 groups of 10/group consisting of a control group, ethanol-only group, nicotine-only group, and a combined ethanol and nicotine group; treatments occurred for 64 days. RESULTS: Exposure to chronic ethanol and nicotine induced CYP2D across various brain regions and cell types, particularly when both drugs were given in combination. No changes in protein levels were observed in liver or in CYP2D mRNA levels in liver and brain. CONCLUSIONS: Ethanol and nicotine increase brain CYP2D levels, which may affect CNS drug response, neurodegeneration and personality among those exposed to alcohol and/or nicotine.

CYP2D6 metabolizes a range of centrally acting drugs, neurotoxins, and endogenous neurochemicals. Higher levels of brain, but not liver, CYP2D6 have been identified in alcoholics and smokers, suggesting exposure to ethanol and/or nicotine may induce brain CYP2D6. We investigated the independent and combined effects of chronic ethanol self-administration and nicotine treatment on CYP2D expression. METHODS: Monkeys were randomized into 4 groups of 10/group consisting of a control group, ethanol-only group, nicotine-only group, and a combined ethanol and nicotine group; treatments occurred for 64 days. RESULTS: Exposure to chronic ethanol and nicotine induced CYP2D across various brain regions and cell types, particularly when both drugs were given in combination. No changes in protein levels were observed in liver or in CYP2D mRNA levels in liver and brain. CONCLUSIONS: Ethanol and nicotine increase brain CYP2D levels, which may affect CNS drug response, neurodegeneration and personality among those exposed to alcohol and/or nicotine.