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University of Macau / Faculty of Science and Technology / Department of Electrical and Computer Engineering

M.Tech. / Cardiovascular disease and its complications accounts for about half of all deaths worldwide. As conventional risk factors do not successfully explain all of these cases, homocysteine (Hey) appears to be a new and promising field to investigate as an accompanying risk factor for the development of cardiovascular disease (Stanger et al., 2004). Hyperhomocysteinaemia, or elevated Hey levels, have been shown to be directly linked to the development of cardiovascular disease (Wald and Morris, 2002). Crataegus oxyaeantha Mother Tincture (0) has been used over centuries for various cardiovascular disease conditions and is considered to have cardio-protective properties (Rose and Treadway, 1999), however its effect on homocysteine levels has not been researched. The atm of this double-blind placebo-controlled study was to determine the effect of homoeopathically prepared Crataegus oxyaeantha (J on Hey levels in males aged 25-35 years of age by measuring Hey levels in the blood over a three week period. Participants attended an initial consultation where the procedure of the research was discussed, a short medical history was taken, and a full cardiovascular examination together with vital signs was assessed. Thereafter a pathology laboratory (Lancet laboratories) measured Hey levels of the participants. Those participants that qualified for the study were divided into two groups of fifteen. The experimental group received a 25mL bottle of Crataegus oxyaeantha 0 and the placebo group received a 25mL bottle of alcohol identical in appearance and taste. Participants were informed not to make any substantial changes to their diet and lifestyle. After three weeks a second Hey test was completed and a follow up consultation was scheduled. Collected data was statistically analyzed and a Chi Square goodness of fit test was utilized to determine if there was any significant decrease in Hey levels in the participating individuals. Preliminary findings suggest that Crataegus oxyaeantha (J was not effective in reducing plasma Hey levels in adult males with Hey levels of 6.3 mmoVL and higher, however more research over an extended period of time is needed to confirm these findings.

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Because the many physicians and students of heredity have not been closely associated in finding that the causes of cardiovascular diseases might lie, in a large measure, to an inherited predisposition, this study has been undertaken; first, to contribute to several more case studies of cardiovascular diseases to the knowledge of heredity; second, to find if there is a possible successive occurrence of cardiovascular diseases in generation after generation; and third, to determine a possible mode of transmission from parents to offspring by an analysis of nine genealogies.

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Cardiovascular disease remains the leading cause of death worldwide. A lack of curative treatments and a shortage of transplant hearts necessitate new approaches to cardiac repair. Recent advances, including the advent of pluripotent stem cell-derived cardiomyocytes and the development of tissue engineering techniques, represent promising new directions to remuscularize the heart or induce endogenous regeneration. However, these approaches are currently limited by the immaturity of differentiated cardiomyocytes and the inability of cardiomyocytes to functionally integrate with the damaged myocardium. Mimicking the cardiomyocyte niche, the myriad signals surrounding the cardiomyocyte, may enhance the utility of these cells. In this dissertation, each of the three aspects of the cardiomyocyte niche: physical signals, the extracellular matrix, and soluble factors, are examined for their ability to guide cardiomyocyte growth and function. We first explore the effect of electrical stimulation, a physical signal pervasive in the heart, on pluripotent stem cell-derived cardiomyocyte development and function. Stimulated cardiomyocytes are more mature, show greater cell-cell connectivity, and are more resistant to tachycardic stress. Cardiomyocytes adapt their beating rate to the stimulation frequency, an effect mediated by the emergence of a rapidly depolarizing cell type and ion channel expression. We next engineer cardiovascular tissue architecture, critical components of the extracellular matrix, using a micromolding approach and determine geometric parameters necessary for the induction of cardiomyocyte alignment and tissue synchrony. We finally test pluripotent stem cell-derived cardiomyocyte exosomes, soluble nanovesicles specifically packaged and secreted by the cell, in vitro and in vivo, demonstrating functional improvement and reduction of arrhythmia in the heart. Therefore, the use of the cardiomyocyte niche supports the interrogation of cellular function to enable new cell-based approaches for the reduction of arrhythmia or induction of repair in the heart.

Polyphenols are naturally-occurring phytochemicals, which form an integral part of the human diet. Results from epidemiological studies have associated polyphenol intake with reduced risk of cardiovascular diseases. Previous human intervention studies suggested that dietary polyphenols exert their cardioprotective effects through their antioxidant and anti-inflammatory effects. While most in vitro experiments have not accounted for the bioavailability and metabolism of these polyphenols, our work has provided direct evidence, using quercetin, that metabolic transformation, together with bioavailability, exert profound effects on bioactivity. We examined the effect of quercetin and its major metabolites on the production of pro-inflammatory eicosanoids by human leukocytes. Studies comparing free radical scavenging, antioxidant activity and eicosanoid production demonstrate that there are different structural requirements for antioxidant and anti-inflammatory activity. We also investigated the effect of metabolic transformation on flavonoid bioactivity by comparing the activity of quercetin and its major metabolites to inhibit inflammatory eicosanoid production from human leukocytes. Quercetin was a potent inhibitor of leukotriene B4 formation in leukocytes (IC50 ~ 2µM), and its activity was dependent on specific structural features, particularly the 2,3 double bond of the C ring. Functionalisation of the 3'-OH group with either methyl or sulfate reduced inhibitory activity up to 50% while a glucuronide substituent at the 3-OH effectively removed the leukotriene B4 inhibitory activity. The major quercetin metabolite quercetin-3'-O-sulfate retained considerable lipoxygenase inhibitory activity (IC50 ~ 7 µM) while quercetin-3-O-glucuronide maintained antioxidant activity but had no lipoxygenase inhibitory activity at physiologically relevant concentrations. We conclude that structural modification of quercetin due to metabolic transformation had a profound effect on bioactivity, and that the structural features required for antioxidant activity of 8 quercetin and related flavonoids were unrelated to those required for inhibition of inflammatory eicosanoids.

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Atherosclerosis is a major contributor to cardiovascular disease and accounts for an estimated one third of deaths overall. In order to address the hemodynamic components of disease pathogenesis, researchers have focused on mechanotransduction of flow-dependent shear stress in the vascular endothelium as a source of novel pathological mechanisms. Understanding how unidirectional, laminar blood flow protects vessels from atherogenesis, while disturbed, oscillatory blood flow promotes it, stands to provide enormous insight into disease pathogenesis and may provide powerful, specific new therapies for cardiovascular disease intervention. The overall objective of this dissertation was to determine which microRNAs (miRNAs) and mRNAs are regulated by different flow conditions in vascular endothelial cells in vitro and in mouse carotid artery endothelium in vivo, and to identify which miRNAs mediate flow-dependent vascular inflammation. The overall hypothesis of this project was that oscillatory shear (OS) and laminar shear (LS) stress differentially alter the expression of mechanosensitive miRNAs each capable of regulating complex networks of gene expression, which in turn leads to inflammation in endothelial cells. This hypothesis was tested using both in vitro and in vivo approaches, high throughput microarray analyses, and functional validation of specific targets by PCR. The findings from the partial carotid ligation model show that acute exposure to disturbed flow results in accelerated endothelial dysfunction and atherosclerosis in vivo. High-throughput microarrays reveal distinct expression profiles of both miRNAs and mRNAs in mouse endothelium exposed to disturbed flow suggesting the regulatory mechanisms by which miRNAs regulate mRNAs resulting in EC inflammation, the earliest stage of atherosclerosis. This in vivo study provides new insight into the mechanisms of flow induced atherosclerosis. In particular, the upregulation of miR-663 due to OS in HUVEC causes monocyte adhesion, but not endothelial apoptosis, in an ICAM-1 dependent manner. miR-663 regulates a group of genes including transcriptional factors and inflammatory genes which may also mediate OS-induced EC inflammation. Collectively, revealing the profiles of miRNAs and mRNAs regulated by hemodynamic flow provides a better understanding in vascular diseases and provide potential target for developing effective preventative therapeutic approaches in cardiovascular diseases.