Univ., Diss.--Heidelberg, 2006. / Literaturverz. S. 135 - 160.

Thesis (M.S.)--West Virginia University, 2009. / Title from document title page. Document formatted into pages; contains v, 84 p. : ill. Vita. Includes abstract. Includes bibliographical references (p. 43-47).

Dissertation (Ph.D.)--Auburn University,2007. / Abstract. Vita. Includes bibliographic references (p.90-118).

Thesis (Ph.D.) -- University of Texas at Arlington, 2008.

published_or_final_version / Medicine / Master / Master of Research in Medicine

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Cigarette smoke (CS) is a well-established risk factor to cardiovascular health and the most preventable cause of death. Countless studies have demonstrated its harm to health and many more studies investigating its pathogenic mechanisms. While the CS-induced pathogenic mechanism of cardiovascular dysfunction has been mainly attributed to a combination of oxidative imbalance, vascular endothelial dysfunction, inflammation and modification of lipid profile, the focus of the current study was on the mediators of inflammation and the activation of signal pathways. In this study, we investigated the effects of CS on the pro-inflammatory/anti-inflammatory status in the heart and to elucidate the activation of specific signaling pathways in an in vivo rat model. Male Sprague-Dawley rats were divided into groups of CS exposure and sham air (SA) and exposed to 1 hour of respective CS and SA exposure daily for 56 days. The rats were then sacrificed and the ventricular homogenates were examined. Cardiac pro- inflammatory and anti-inflammatory mediators such as C-reactive protein (CRP), interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (CINC-1), transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF) and IL-10 were measured by enzyme-linked immunosorbent assay (ELISA) and the activation of specific signaling pathways was determined by Western blot analysis. CS caused suppression of cardiac CRP, IL-6, TGF-β1, and IL-10 and elevation of VEGF, revealing the imbalance of pro-inflammatory/anti-inflammatory status. Nuclear factor-κB (NF-κB) was also activated along with the activation of extracellular-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) but not p38 mitogen-activated protein kinase (MAPK) after 56 days of CS exposure. These data suggests the presence of a local adaptive mechanistic response to modulate cardiac pro-inflammatory/anti-inflammatory status via NF-κB/MAPK pathways after exposure to CS. These findings shed insight into the mechanistic pathways of CVD progression, allowing possible identification of selected mediators as biomarkers that could benefit early detection of CVD arisen from cigarette smoking. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

Background Cardiovascular disease (CVD) is the worldwide leading cause of death among non-communicable diseases and results in a huge burden of mortality and morbidity. China, a rapidly growing East Asian country, has the world largest population and is facing an increasing burden. Incidence of CVD is lower in China than in Western countries. There are more strokes, especially hemorrhagic strokes, but less coronary heart disease (CHD) in China than in Western countries. Statin, a first-choice drug for lowering low-density lipoprotein cholesterol (LDL-C), has been shown to be effective in preventing CVD and is widely used in Western countries. However, it is not known whether the same can be applied to Asian countries, where the incidence of CVD is lower and ischemic events are rarer. The aim of this systematic review is to evaluate the effectiveness of statin for prevention of CVD in East Asian populations. Methods A systematic review was conducted by searching for randomized controlled trials from 3 databases (PubMed, MEDLINE and Cochrane Trial) for prevention of CVD comparing statin with usual care or placebo in East Asian population. Data on CVD events (deaths, CHD and cerebrovascular events, rehospitalization and revascularization) and serum lipid levels (total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG)) were extracted. Risk ratios of CVD events and change in serum lipid level were tabulated. The relationship between change in serum lipid level and mortality and incidence of CVD events were also explored. Results Fourteen studies were included, with most of them (9 studies) done in Japan. Overall, statins did not significantly reduce risk of mortality, CHD events, cerebrovascular events, revascularization and rehospitalization due to CHD. However, statins consistently lowered the risk of angina-related rehospitalization by 53% (95% confidence interval (CI) 23% to 71%) and 64% (95% CI 11% to 86%) respectively in 2 studies. There was a consistent reduced risk of composite CVD events by 34% (95% CI 5% to 55%) to 54% (95% CI 6% to 41%) in 4 studies for secondary prevention. In terms of change in lipid levels, TC and LDL-C were significantly reduced by 8% to 31% and 14% to 41% respectively with statin treatment. Change in HDL-C and TG were not consistent across studies. Lowering of TC and LDL-C level was correlated with the reduction in composite CVD and CHD events. Conclusion The use of statins in East Asian populations to prevent CVD may not be as effective as in Western countries, because of the lower baseline risk and different patterns of CVD. As the prevalence of CVD risk factors increases, the incidence of CVD will increase and the pattern of CVD may change, so careful monitoring is needed. More importantly, most of the studies included had small sample sizes, short follow-up periods and/or low methodological quality, which might contribute to the inconsistent findings. A further large-scale randomized controlled trial should be done to confirm the benefits of statins among Chinese. / published_or_final_version / Public Health / Master / Master of Public Health

Diabetic cardiomyopathy (DCM), a disorder of the heart muscle, is one of the major and most rampant culprits claiming thousands and thousands of lives around the globe every year by interfering with the blood circulation and causing the development of heart failure eventually. The progression of the disease is asymptomatic and having a long latent period, and it is characterized functionally by ventricular dilation, diastolic dysfunction, interstitial fibrosis and cardiomyocytes hypertrophy. It was suggested the pathogenesis of the disease and the related complications are related to the effects of hyperglycemia on cardiomyocytes. So understanding the physiology of both the normal and pathological conditions, and the underlying mechanisms involved are of paramount importance to derive therapies to cope with this disease. However, it is difficult, if not impossible, to study the physiology in vivo using a live sample or to build a cellular model with adult cardiomyocytes due to the insufficient number of the cells harvested. This is not until the emergence of Embryonic Stem Cells (ESCs) that a cellular model with clinical sufficient number of cardiomyocytes could be built for investigation and drug screening. With a view to mimicking the situation of the Diabetic cardiomyopathy of the Type II Diabetes mellitus (DM) patients, mouse ESCs are used to differentiate into cardiomyocytes using the traditional hanging drop method to produce Embryoid body (EB). The cardiomyocytes were then enriched and plated so that different testing conditions could be applied. The effect of high glucose (HG), Insulin and the combination of high glucose and insulin were then analyzed. This was to show the significance of hyperglycemia, hyperinsulinemia due to insulin resistance and the role of insulin in hyperglycemia on cardiomyocytes respectively. The results agreed with previous findings that high glucose and insulin alone do induce cells apoptosis while the combination of insulin and glucose did decrease the number of apoptosis and while the co-culture of insulin with High dosage of glucose has shown to reduce the effect of hypertrophy. / published_or_final_version / Medicine / Master / Master of Medical Sciences

Despite major advances in diagnosis and prevention of coronary artery disease (CAD), the development of therapies to regenerate functional cardiomyocytes after myocardial infarction (MI) is very challenging. Studies have demonstrated that bone marrow derived mesenchymal stem cells (BM-MSCs) secrete a panel of growth factors and anti-inflammatory cytokines to activate resident cardiomyocytes and cardiac stem cells in myocardial repair after MI. However, the mechanisms of modulating BM-MSC secretions are not well understood. Recently, molecular candidates in regulating BM-MSCs paracrine secretion to improve cardiac protection have been explored. Amongst the molecular candidates, Nuclear casein kinase and cyclin-dependent kinase substrate 1 (Nucks1) is suggested as a regulatory protein in nuclear factor-kappa B (NF-κB) signaling pathway by interacting with TANK-binding kinase 1 (TBK1). TBK1 is a non-canonical I kappa B (IκB) kinase that can activate the NF-κB transcription factor and its transcriptional response. NF-κB signaling pathway controls many cellular responses such as cell survival, proliferation and cytokine productions. We hypothesizes Nucks1 may have potential roles in regulating mouse BM-MSCs secretion of growth factors and cytokine profiles in heart repairs after MI. To test our hypothesis, the cardiac protection efficacy of acute infarcted mouse myocardium was measured after the transplantation of WT versus Nucks1 KO BM-MSCs. To this end, we developed a mouse model of acute myocardial infarction (AMI) induced by ligation of left descendant coronary artery. Acute infarcted mouse myocardium receiving WT or Nuck1 KO BM-MSCs transplantation, demonstrated a significant improvement of left ventricular ejection fraction (LVEF), ESP, +dP/dt, ESPVR and vessel density, and reduced infarction size in comparison with PBS control group post-4 weeks of transplantation. Furthermore, acute infarcted mouse myocardium receiving Nucks1 KO BM-MSCs transplantation provided better cardioprotective effects than those receiving WT BM-MSCs transplantation. Immunostaining disclosed CD31 and smooth muscle actin (SMA) expression in acute infarcted mouse myocardium receiving Nucks1 KO BM-MSCs were relatively higher than those receiving WT BM-MSCs transplantation. Additionally, a distinct secretion profile of growth factors and cytokines between Nucks1 KO BM-MSCs versus WT BM-MSCs under in vitro ischemia was studied. Expression of vascular endothelial growth factor alpha (VEGFα) in Nucks1 KO BM-MSCs under hypoxia/ serum deprivation was significantly higher than that of WT BMMSCs. Taken together, our data suggested BM-MSCs provide cardiac protection in acute infarcted myocardium. Transplantation of Nucks1 KO BMMSCs may further enhance the cardiac repair of the acute infracted myocardium through an induction of VEGFα. / published_or_final_version / Medicine / Master / Master of Philosophy