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Browsing by Author "Johnson, Sarah A., advisor"

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    Cardiovascular-protective effects of blueberry consumption in postmenopausal women with above-normal blood pressure
    (Colorado State University. Libraries, 2023) Woolf, Emily K., author; Johnson, Sarah A., advisor; Gentile, Christopher L., committee member; Weir, Tiffany L., committee member; Rao, Sangeeta, committee member
    Endothelial dysfunction is the first step in atherosclerosis and contributes to its progression, and thus, is central to cardiovascular disease (CVD). It is driven by excessive oxidative stress and inflammation and characterized by impaired endothelium-dependent dilation. Estrogen-deficient postmenopausal women have oxidative stress-mediated suppression of endothelial function that is worsened by high blood pressure. Chronic blueberry consumption may be a beneficial dietary intervention for this population as it has shown to improve vascular function and blood pressure, though some studies have not demonstrated efficacy possibly due to the observed high interindividual variability in response to the intervention. Evidence indicates blueberries improve endothelial function, but studies have not been performed in postmenopausal women. Furthermore, ex vivo research has shown that blueberry (poly)phenols and their metabolites can decrease endothelial oxidative stress and inflammation, but whether these mechanisms translate to humans is unclear. The objectives of this dissertation were to 1) examine the efficacy of chronic blueberry consumption to improve endothelial function and blood pressure in estrogen-deficient postmenopausal women with above-normal blood pressure, with a specific focus on identifying mechanisms for improving endothelial function, 2) identify factors that contributed to the efficacy of blueberries as a dietary intervention for improving endothelial function, and 3) explore cellular mechanisms responsible for endothelial function improvements and the anti-atherogenic potential of blueberries. To investigate the aforementioned, we conducted a randomized, double-blind, placebo-controlled clinical trial and assessed endothelial function (measured through flow-mediated dilation (FMD)) and supine brachial blood pressure before and after daily consumption of 22 g of freeze-dried highbush blueberry powder or isocaloric placebo powder for 12 weeks. To examine mechanisms for improved endothelial function, FMD was assessed before and after infusing a supraphysiological dose of the antioxidant ascorbic acid (i.e. vitamin C) and normalized to shear rate area under the curve (FMD/SRAUC). To investigate factors impacting the interindividual variability in the endothelial function responses after the 12 weeks of blueberry consumption, we grouped the blueberry treatment group into responders (≥ +1% unit Δ FMD) and non-responders (< +1% unit Δ FMD) and performed secondary statistical analyses using data produced from the clinical trial. Lastly, to investigate mechanisms for improvements in endothelial function, we used a reverse translational human-to-cell approach leveraging human blood serum collected from participants in the clinical trial to perform ex vivo cell culture experiments. Results from the clinical trial showed that daily blueberry consumption significantly improved FMD/SRAUC compared to baseline by 96%. FMD not normalized for shear rate increased by 1.34% though the effects were not statistically significant (but were clinically significant). Improvements in FMD/SRAUC after blueberry consumption were due to reductions in oxidative stress as responses to ascorbic acid infusion were significantly reduced at 12 weeks in the blueberry group compared to baseline, with no changes in the placebo group. There were no major effects on blood pressure, arterial stiffness, endothelial cell protein expression, or other blood biomarkers of cardiovascular health. It was determined that the blueberry intervention was ~50% effective for improving FMD to clinically relevant levels of ≥ +1%, and that responders had decreased cardiovascular health and higher levels of circulating estrogen at baseline compared to non-responders. After 12 weeks of blueberry consumption, responders had reductions in oxidative stress, lower plasma nitrate levels, and higher phosphorylated endothelial nitric oxide synthase protein expression compared to non-responders. Lastly, we cultured HAECs with 15% serum (blueberry and placebo) for 1 h followed by 200 µM hydrogen peroxide (H2O2) for 24 h to induce endothelial dysfunction and evaluated the effects of blueberry (poly)phenol-rich serum on endothelial cell dysfunction and atherosclerosis progression. There were no statistically significant differences on monocyte binding, insulin-stimulated nitric oxide production, or peroxynitrite concentrations between dysfunctional HAECs treated with blueberry and placebo serum from the clinical trial. Collectively, results from these studies indicate that daily blueberry consumption for 12 weeks improves endothelial function in postmenopausal women with above-normal blood pressure through reductions in oxidative stress, and that efficacy (i.e. degree to which postmenopausal women responded to treatment in endothelial function) seems to be dependent on participant characteristics including cardiovascular risk factors and estradiol at baseline. Due to the inconclusive results regarding the ex vivo experiment, cellular mechanisms by which blueberry (poly)phenol metabolites impact endothelial function and atherosclerosis progression cannot be determined.
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    The efficacy of red beetroot juice supplementation to improve cardiometabolic health in middle-aged/older adults with overweight or obesity
    (Colorado State University. Libraries, 2019) Litwin, Nicole S., author; Johnson, Sarah A., advisor; Pagliassotti, Michael J., committee member; Seals, Douglas R., committee member; Gentile, Christopher L., committee member; Rao, Sangeeta, committee member
    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in developed societies worldwide. Advancing age is the primary risk factor for CVD, with lifestyle factors such as diet and nutrition also playing a role. Aging results in adverse changes to the arteries including vascular endothelial dysfunction which is characterized by a decline in nitric oxide (NO)-mediated endothelium-dependent dilation, and increased stiffening of large elastic arteries. This age-associated vascular dysfunction is predominantly driven by increased oxidative stress and chronic inflammation and contributes to the development of CVD through the development of atherosclerotic plaque and hypertension. Previous research suggests that a single high-fat meal may result in transient impairments in postprandial vascular endothelial function, which is thought to be driven by a postprandial pro-inflammatory and oxidative stress response to hypertriglyceridemia and/or hyperglycemia, resulting in a decline in NO bioavailability. This phenomenon may be exaggerated in aging individuals with overweight or obesity, though previous research findings have been inconclusive. Nonetheless, repeated high-fat meal consumption may increase CVD risk through impairments in postprandial vascular endothelial function, thus warranting further investigation. While the mechanisms of postprandial vascular endothelial dysfunction continue to be fully elucidated, an emerging area of research suggests that the oral microbiota may determine steady-state NO levels. Recent scientific discoveries indicate that the oral microbiota reduces dietary inorganic nitrate to nitrite and NO (known as the enterosalivary nitrate-nitrite-NO pathway), thus providing a new therapeutic target for CVD risk management. Red beetroot juice is a rich source of inorganic nitrate as well as other bioactive compounds such as betalains, flavonoids, carotenoids, and ascorbic acid, and previous research suggests that it may improve several parameters of cardiometabolic health including vascular endothelial function. The goals of this dissertation research were to 1) examine the clinical efficacy of acute and chronic red beetroot juice supplementation on postprandial vascular endothelial function after a high-fat meal challenge in middle-aged/older men and postmenopausal women with overweight or obesity, and 2) investigate the underlying mechanisms that contribute to vascular and metabolic responses to the meal challenge and supplementation, including the nitrate-dependent and -independent effects of red beetroot juice. To investigate the aforementioned, we conducted a randomized, double-blind, placebo-controlled, 4-period, crossover, clinical trial. To investigate the nitrate-dependent and -independent effects of red beetroot juice, we used 1) a placebo concentrate devoid of inorganic nitrate or polyphenols, 2) red beetroot juice concentrate, 2) nitrate-depleted red beetroot juice concentrate, and 4) a placebo concentrate with an equivalent dose of inorganic nitrate to that of red beetroot juice. We first examined the impact of acute and chronic red beetroot juice supplementation on postprandial vascular endothelial function and other cardiometabolic responses to a high-fat meal challenge. We found that the high-fat meal led to postprandial alterations in several cardiometabolic parameters but did not impair vascular endothelial function. Significant acute and chronic increases in saliva and plasma NO metabolites were observed following consumption of red beetroot juice and the placebo plus inorganic nitrate, but these increases were not paralleled by significant changes in vascular endothelial function. Although the meal and treatments altered several other parameters of cardiometabolic health, there were no consistent effects of the treatments on those parameters. Next, we examined the relationship between oral nitrate-reducing bacteria and NO metabolites following acute and chronic red beetroot juice supplementation to gain insight on the impact of the oral microbiota on dietary nitrate metabolism and vascular responses to the high-fat meal. We found that red beetroot juice and inorganic nitrate salt supplementation may alter the oral microbiome to favorably affect NO metabolism and vascular endothelial function in this population. Taken together, these results suggest that although red beetroot juice did not modulate postprandial vascular endothelial function, it may be a promising dietary intervention for targeting the enterosalivary nitrate-nitrite-NO pathway to increase NO bioavailability in middle-aged/older adults with overweight or obesity. Further research is needed to evaluate the potential of red beetroot juice as an oral microbiota targeted therapy for improving NO bioavailability and overall cardiovascular health. Additionally, further research is needed to better understand the impact of high-fat meal consumption on cardiometabolic health.