Cardiovascular Diseases Commons^™

Lipoprotein(A), Oxidized Phospholipids, And Vascular Smooth Muscle Cell Phenotype And Viability, Michael Dunphy

Electronic Thesis and Dissertation Repository

Genetic studies have shown elevated plasma lipoprotein(a) (Lp(a)) levels to be an independent and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease, however a definite mechanism for this pathogenicity has yet to be clearly identified. Oxidized phospholipids (oxPLs) have been implicated in facilitating atherogenic changes in the gene expression of vascular cells. As the primary carrier of oxPLs in the plasma, we hypothesize that Lp(a) contributes to vascular diseases by its enhanced ability to bind to and deliver oxPLs to tissue through a strong lysine binding site on its apolipoprotein(a) (apo(a)) component. Using a cultured primary …

The Impact Of Volatile Organic Compound Exposure On Subclinical Biomarkers Of Cardiovascular Injury., Breandon Taylor

Electronic Theses and Dissertations

Pollution has been identified as the leading environmental cause of non-communicable disease and premature deaths globally. Volatile organic compounds (VOCs) are gaseous chemical constituents of pollution derived from a variety of sources, including industrial solvents and byproducts, automobile exhaust, tobacco smoke, cleaning supplies, and personal care products. VOCs are also abundant at various Superfund and Hazardous Waste Sites. Emerging data suggest that VOC exposure is associated with several adverse health outcomes, including cardiovascular disease (CVD). VOCs and their metabolites can potentially damage the endothelial lining of blood vessels, resulting in perturbed vascular function and vascular inflammation. We hypothesize that VOC …

Mechanism Of Rare Variant In Acta2, P.Arg149cys, Driving Diverse Vascular Disease, Kaveeta Kaw

Dissertations & Theses (Open Access)

Heterozygous variants in ACTA2 (smooth muscle (SM) α-actin) predispose to thoracic aortic aneurysms and dissections (TAAD) and early-onset coronary artery disease (CAD). The most common ACTA2 mutation is a genetic alteration of arginine 149 to a cysteine, ACTA2 p.Arg149Cys, which accounts for disease in 24% of all ACTA2 mutation carriers.(1) ACTA2 p.Arg149Cys mutation carriers present with either TAAD or CAD but rarely have both diseases. To identify the molecular mechanisms dictating whether an individual with ACTA2 p.Arg149Cys develops TAAD or CAD, CRISPR/Cas9 technology was used to generate the mutant mouse, Acta2^R149C/+, in a C57BL6 background. Acta2^R149C/+ mice …

Endothelial Cell-Specific Loss Of Breast Cancer Susceptibility Gene 2 Exacerbates Atherosclerosis, David C.R. Michels

Electronic Thesis and Dissertation Repository

Despite mounting concern over the increased risk of cardiovascular disease in breast cancer patients, studies evaluating the common genetic/molecular link between these diseases are limited. Mutations in the breast cancer susceptibility genes (BRCA1&2) predispose carriers to breast and ovarian cancers due to compromised DNA damage repair capacity leading to DNA damage accumulation; in cancer cells, and in other cell-types including endothelial cells, causing atherosclerotic hallmarks of endothelial dysfunction/apoptosis. We present a new understanding of BRCA2’s protective functionality in the setting of atherosclerosis. Studies have thus far demonstrated that while loss of endothelial BRCA2 in mice does not affect a molecular …

Does Epa Cause A Decrease In Inflammation Of Bend.3 Cells Through Ffar4?, Clay J. Weidenhamer

Masters Theses

Atherosclerosis is an inflammatory disease initiated by low and oscillatory shear stress on the endothelium. The inflammatory process recruits leukocytes to the vessel wall by expression of the adhesion molecule VCAM-1. Activation of the NF-κB inflammatory signaling pathway is responsible for the increase in VCM-1 expression. Omega 3 FAs, such as EPA, reduce the risk of atherosclerosis by decreasing this inflammatory response. The pathway by which omega 3 FAs is proposed to inhibit inflammation includes activating FFAR4 to decrease NF-κB activation thereby reducing expression of adhesion molecules. We hypothesized that treatment of endothelial cells with 30 μM EPA would decrease …

Finding The Balance​ The Effects Of Α-Cyclodextrin, 2-Hydroxypropyl-Β-Cyclodextrin, And Cholesterol Bacteroides Vulgatus And Clostridium Bolteae​, Bethany Weaver

Pence-Boyce STEM Student Scholarship

Atherosclerosis is a cardiovascular disease that is characterized by the hardening of arteries through the formation of cholesterol plaques. Cyclodextrins could potentially treat atherosclerosis by shrinking plaques. These cyclic oligosaccharides can make complexes with cholesterol but have also shown toxic side effects. This study looked for potential negative effects of cyclodextrins and cholesterol on gut bacteria. It was hypothesized that Bacteroides vulgatus will have decreased growth when grown in broth with cholesterol. In contrast, Clostridium bolteae will have decreased growth when grown in broth with cyclodextrins. Due to the fact that these bacteria are anaerobic, Clostridium bolteae and Bacteroides vulgatus …

Assessing The Structure-Function Relationships Of The Apolipoprotein(A) Kringle Iv Sub-Type 10 Domain, Matthew J. Borrelli

Electronic Thesis and Dissertation Repository

Elevated plasma lipoprotein(a) (Lp(a)) is the most prevalent heritable risk factor in the development of cardiovascular disease. The apolipoprotein(a) (apo(a)) component of Lp(a) is strongly implicated in the pathogenicity of Lp(a). It is hypothesized that the inflammatory potential of Lp(a)/apo(a) is mediated by the lysine binding ability of the apo(a) kringle IV10 (KIV10) domain, along with its covalently bound oxidized phospholipid (oxPL). Using targeted mutagenesis, two novel null alleles for the LPA gene that generate non-secretable apo(a) species have been identified, resulting from amino acid substitutions in the KIV10 domain. A potential mechanism by which KIV10 oxPL modification is enriched …

Attenuation Of Obesity, Hepatic Steatosis And Reversal Of Atherosclerosis By The Flavonoids Naringenin And Nobiletin, Amy C. Burke

Electronic Thesis and Dissertation Repository

Naringenin and nobiletin are naturally-derived citrus flavonoids that have significant lipid-lowering and insulin sensitizing effects in vitro and in vivo. In murine models of obesity, metabolic dysfunction and atherogenesis, these flavonoids protect against the development of cardiometabolic disease. However, the ability of naringenin and nobiletin to reverse existing metabolic dysfunction and atherosclerosis has not been investigated.

The purpose of this thesis was to investigate the ability of the citrus flavonoids, naringenin and nobiletin, to reverse obesity, metabolic syndrome and atherosclerosis in two different mouse models of atherosclerosis regression. The first chapter demonstrates in Ldlr^-/- mice with diet-induced obesity, …

Knockdown Of Heparan Sulfate Via Ndst1 Knockout Does Not Inhibit Mouse Aortic Endothelial Cell Alignment In-Vivo, John Diaz De Leon Iii

Dissertations and Theses

Atherosclerotic plaque localizes in predictable areas such as arches and bifurcations which are characterized by disturbed flow patterns and the resulting damage and dysfunction to the endothelium. Endothelial cells (ECs) under sustained laminar flow align in the direction of flow; however, under disturbed flow conditions, ECs sustain damage to their glycocalyx (GCX) which results in unaligned and rounder cells. An investigation into the role of NDST1 sulfation of heparan sulfate (HS), a key component of many proteoglycans which make up the GCX, was conducted. The descending aortas (DAs) of transgenic mice with conditional knockouts (KOs) of NDST1 in vascular ECs …

Role Of Cannabinoid Receptor Type 2 (Cb2) In Late Stage Atherosclerosis, Makenzie Fulmer

Electronic Theses and Dissertations

Atherosclerosis is a chronic inflammatory disorder of medium and large vessels. Immune signaling and dyslipidemia are two of several processes which influence lesion development in atherosclerosis. Cannabinoids, such as those found in marijuana, exert their effects through two cannabinoid receptors, CB1 and CB2. Recent studies using CB2 knockout mice and CB2-selective ligands have shed light on a protective role of CB2 in early stages of atherosclerosis. However, the role of CB2 in advanced stages of atherosclerosis remains unclear. To determine if CB2 plays a role in advanced atherosclerotic lesion composition and progression, we investigated the effects of systemic CB2 gene …

Effect Of Cannabinoids On Osteogenic Differentiation Of Cultured Vascular Smooth Muscle Cells, Bree A. Eccles

Undergraduate Honors Theses

Vascular calcification is strongly correlated with the clinical manifestations of atherosclerosis, heart attacks and strokes. The calcification process resembles bone formation and involves the osteogenic trans-differentiation of smooth muscles cells within the arterial wall. Cannabinoid receptors are known to modulate bone formation and are present in atherosclerotic vessels, suggesting they may also play a role in modulating calcification. Therefore, we evaluated the effects of cannabinoids on the expression of osteogenic proteins by vascular smooth muscle cells undergoing calcification.

Mimicking The Arterial Microenvironment With Peg-Pc To Investigate The Roles Of Physicochemical Stimuli In Smc Phenotype And Behavior, William G. Herrick

Doctoral Dissertations

The goal of this dissertation was to parse the roles of physical, mechanical and chemical cues in the phenotype plasticity of smooth muscle cells (SMCs) in atherosclerosis. We first developed and characterized a novel synthetic hydrogel with desirable traits for studying mechanotransduction in vitro. This hydrogel, PEG-PC, is a co-polymer of poly(ethylene glycol) and phosphorylcholine with an incredible range of Young’s moduli (~1 kPa - 9 MPa) that enables reproduction of nearly any tissue stiffness, exceptional optical and anti-fouling properties, and support for covalent attachment of extracellular matrix (ECM) proteins. To our knowledge, this combination of mechanical range, low …

Regulation Of C-Reactive Protein Gene Expression And Function, Avinash N. Thirumalai

Electronic Theses and Dissertations

Human C-reactive protein (CRP) is the prototypic acute phase protein whose serum concentration increases rapidly during inflammation. CRP is also associated with atherosclerosis; it is deposited at lesion sites where it may interact with modified lipoproteins. There are 2 major questions regarding CRP: 1. How is the serum concentration of CRP regulated? 2. What are the functions of CRP in atherosclerosis?

Our first aim was to determine the role of the constitutively expressed transcription factor Oct-1 in regulating CRP gene expression. We found that Oct-1 overexpression inhibited (IL-6+IL-1β)- induced CRP gene expression; maximal inhibition required the binding of Oct-1 to …

Effects Of An Angiotensin Ii Type 1 Receptor Blocker On Cardiovascular Calcification, Zachary B. Armstrong

Electronic Thesis and Dissertation Repository

Aims: Three types of cardiovascular calcification are commonly found in humans: arterial calcification, intimal calcification, and calcific aortic valve disease. Very little is known about the mechanisms driving cardiovascular calcification despite serious clinical implications and a clear association with morbidity and mortality. Indeed, it is even unclear whether the same factors are involved in arterial, intimal, and valvular calcification. The objective of this study was to elucidate the effects of an angiotensin II type 1 receptor blocker (ARB) on the progression of cardiovascular calcification in male New Zealand White rabbits. Where appropriate, statins were examined in conjunction and in combination …

The Role Of Angiotensinogen In Atherosclerosis And Obesity, Congqing Wu

Theses and Dissertations--Nutritional Sciences

Angiotensinogen is the only known precursor in the renin-angiotensin system, a hormonal system best known as an essential regulator of blood pressure and fluid homeostasis. Angiotensinogen is sequentially cleaved by renin and angiotensin- converting enzyme to generate angiotensin II. As the major effector peptide, angiotensin II mainly function through angiotensin type 1 receptor.

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and more recently renin inhibitors are widely known as the 3 classic renin-angiotensin system inhibitory drugs against hypertension and atherosclerosis. Here, we developed an array of regents to explore the effects of angiotensinogen inhibition. First, we demonstrated that genetic deficiency of …

Regulation Of Lipid Homeostasis, Inflammatory Signalling And Atherosclerosis By The Peroxisome Proliferator-Activated Receptor Delta, Lazar A. Bojic

Electronic Thesis and Dissertation Repository

The peroxisome proliferator-activated receptor (PPAR) δ is a ligand-dependent transcription factor that has been implicated in metabolic and inflammatory regulation. The molecular and physiological mechanisms by which PPARδ activation regulates lipid metabolism, inflammatory signaling and protection from atherosclerosis in states of metabolic disturbance such as insulin resistance and dyslipidemia, were investigated in a series of in vitro and in vivo studies. In vitro experiments demonstrated that PPARδ activation inhibits atherogenic lipoprotein-induced lipid accumulation and the associated proinflammatory responses. The primary mechanisms for these effects were increased fatty acid β-oxidation, decreased lipoprotein lipase (LPL) activity, reduced MAPK signaling and improved insulin …

Three-Dimensional Ultrasound Measurements Of Carotid Atherosclerosis In Vulnerable Patient Populations, Daniel N. Buchanan

Electronic Thesis and Dissertation Repository

Atherosclerosis is a progressive disease that leads to plaque development and is associated with cardiovascular events such as myocardial infarction and stroke. Several biomarkers have been established as surrogates of plaque development yet none can provide direct, noninvasive, rapid measurements of atherosclerotic disease. Three-dimensional Ultrasound (3DUS) image acquisition is safe, inexpensive and fast, however 3DUS image measurements are limited due to time consuming manual image analyses. In addition, the true clinical meaning of 3DUS carotid imaging measurements has not yet been established. A semi-automated approach for the estimation of 3DUS Total Plaque Volume (TPV) was developed with similar variability and …

Characterization Of The Mechanism Of Pparγ-Mediated Neointima Formation In Rodents, Ryoko Tsukahara

Theses and Dissertations (ETD)

Lysophosphatidic acid (LPA) and its ether analog alkyl glycerophosphate (AGP) elicit arterial wall remodeling when applied intralumenally into the uninjured carotid artery. LPA is the ligand of eight GPCRs and the peroxisome proliferator-activated receptor γ (PPARγ). We pursued a gene knockout strategy to identify the LPA receptor subtypes necessary for the neointimal response in a non-injury model of carotid remodeling and also compared the effects of AGP and the PPARγ agonist rosiglitazone (ROSI) on balloon injury-elicited neointima development. In the balloon injury model AGP significantly increased neointima; however, rosiglitazone application attenuated it. AGP and ROSI were also applied intralumenally for …

Autoimmune Responses To Atherosclerotic Lipids: A Study In Murine Models Of Atherosclerosis And Obesity, Hanjing Wu

Dissertations & Theses (Open Access)

Atherosclerosis is a chronic, complex arterial disease characterized by intimal lipid accumulation and inflammation. A unique lipid-binding molecule, namely cluster of differentiation 1d (CD1d), may impact atherosclerosis. Structurally, CD1d acts as a nonpolymorphic cell-surface receptor, resembling the major histocompatibility complex-I (MHC-I). While MHC-I restricts peptide antigen presentation to T cells, CD1d presents lipid antigens to T cells named CD1d-restrictedd T cells. Although increased expression of CD1d has been found in human plaques, the exact nature of CD1d-recognized lipids in atherosclerosis remains to be determined. Three groups of lipids may undergo oxidation in atherosclerosis producing atherogenic lipids: phospholipids, fatty acids, and …