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Item Atherosclerosis Imaging with 18F-Sodium Fluoride PET(MDPI, 2020-10-20) Høilund-Carlsen, Poul F.; Piri, Reza; Constantinescu, Caius; Iversen, Kasper Karmark; Werner, Thomas J.; Sturek, Michael; Alavi, Abass; Gerke, Oke; Anatomy and Cell Biology, School of MedicineThe evidence on atherosclerosis imaging with 18F-sodium-fluoride (NaF) positron emission tomography (PET) is hotly debated because of the different patient characteristics, methodology, vascular beds, etc. in reported studies. This review is a continuation of a previous review on this topic, which covered the period 2010–2018. The purpose was to examine whether some of the most important questions that the previous review had left open had been elucidated by the most recent literature. Using principles of a systematic review, we ended analyzing 25 articles dealing with the carotids, coronary arteries, aorta, femoral, intracranial, renal, and penile arteries. The knowledge thus far can be summarized as follows: by targeting active arterial microcalcification, NaF uptake is considered a marker of early stage atherosclerosis, is age-dependent, and consistently associated with cardiovascular risk. Longitudinal studies on NaF uptake, conducted in the abdominal aorta only, showed unchanged uptake in postmenopausal women for nearly four years and varying uptake in prostate cancer patients over 1.5 years, despite constant or increasing calcium volume detected by computed tomography (CT). Thus, uncertainty remains about the transition from active arterial wall calcification marked by increased NaF uptake to less active or consolidated calcification detected by CT. The question of whether early-phase atherosclerosis and calcification can be modified remains also unanswered due to lack of intervention studies.Item Death-Associated Protein Kinase Regulates Vascular Smooth Muscle Cell Signaling and Migration(2011-03-16) Blue, Emily Keller; Gallagher, Patricia J.; Elmendorf, Jeffrey S.; Herring, B. Paul; Rhodes, Simon J.; Thurmond, Debbie C.Cardiovascular disease is the number one cause of death for Americans. New treatments are needed for serious conditions like atherosclerosis, as it can lead to stroke and heart attack. Many types of cells contribute to the progression of cardiovascular disease, including smooth muscle cells that comprise the middle layers of arteries. Inappropriate growth and migration of smooth muscle cells into the lumen of arteries has been implicated in vascular diseases. Death associated protein kinase (DAPK) is a protein that has been found to regulate the survival and migration of cancer cells, but has not been well characterized in vascular cells. The objective of this work was to determine the signaling pathways that DAPK regulates in smooth muscle cells. These studies have focused on smooth muscle cells isolated from human coronary arteries (HCASM cells). We have determined that HCASM cells depleted of DAPK exhibit more rapid migration, showing that DAPK negatively regulates migration of vascular cells. Results from a focused RT-PCR array identified matrix metalloproteinase 9 (MMP9) as a gene that is increased in cells depleted of DAPK. MMP9 is an important enzyme that degrades collagen, a component of the extracellular matrix through which smooth muscle cells migrate during atherosclerosis. We found that DAPK regulates phosphorylation of the NF-kappa B transcription factor p65 at serine 536, a modification previously found to correlate with increased nuclear levels and activity of p65. In DAPK-depleted HCASM cells, there was more phosphorylation of p65, which causes increased MMP9 promoter activity. Additional experiments were conducted using transgenic mice in which the DAPK gene has been deleted. By studying these mice, we have determined that under some circumstances DAPK augments maximal MMP9 levels in mouse carotid arteries which have been injured by ligation surgery via other signaling pathways. MMP9 has been previously implicated as a protein that promotes vascular diseases such as atherosclerosis. Our research in identifying DAPK as a regulator of MMP9 expression identifies a new target for treatment of vascular diseases like atherosclerosis.Item Depressive Symptom Severity, Stressful Life Events, and Subclinical Atherosclerosis in African American Adults(2015) Berntson, Jessica; Stewart, Jesse; Cyders, Melissa Anne; Rand, Kevin L.; Grahame, Nicholas J.Prospective epidemiologic evidence indicates that both stressful life events (SLEs) and depression are associated with an increased risk of subclinical atherosclerosis and cardiovascular disease (CVD) events. Even though stressful life events (SLEs) and depression co-occur and may act together to influence cardiovascular disease (CVD) risk, these psychosocial factors have been mainly examined in isolation. For instance, depression may moderate the relationship between SLEs and CVD outcomes. I hypothesized that depressive symptoms would potentiate the deleterious effect of SLEs on subclinical atherosclerosis. This hypothesis is plausible, given that depressed adults exhibit exaggerated and prolonged sympathetic nervous system, hypothalamic-pituitary-adrenal (HPA) axis, and inflammatory responses to stress, which in turn could promote atherosclerosis. As compared to their nondepressed counterparts, depressed individuals may also be more likely to engage in maladaptive methods to cope with SLEs (e.g., increased tobacco use, alcohol use, and consumption of low-nutrient, energy dense foods), which could also promote atherosclerosis. I examined cross-sectional data from 274 to 279 (depending on the outcome measure) older, African American adults (mean age = 66 years, 67% female) with no evidence of clinical CVD or dementia who participated in the St. Louis African American Health-Heart study (2009–2011). Number of SLEs was assessed using the Life Events Calendar, a structured interview. From this interview, a continuous SLEs variable was computed (number of adult SLEs: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11+). Severity of depression symptoms was measured using the 17-item Hamilton Rating Scale for Depression (HAM-D). Two measures of subclinical atherosclerosis were obtained: carotid intima-media thickness (CIMT; assessed by ultrasonography) and coronary artery calcification (CAC; assessed by multi-detector computerized tomography). I conducted linear (CIMT) and logistic (CAC) regression models, first adjusted for demographics (age, sex, education) and then fully-adjusted (demographics; mean arterial pressure; low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C); hemoglobin A1c; BMI; tobacco use; diabetes diagnosis; and use of antihypertensitve, lipid lowering, antidiabetic, and antidepressant medications). No main effects of SLEs or HAM-D were found for CIMT or CAC. There were also no SLEs by HAM-D interactions for CIMT or CAC. Because the current results are largely inconsistent with prior literature and there is a paucity of studies utilizing African American samples, future research is needed to examine the independent and interactive associations of SLEs and depressive symptoms with measures of subclinical atherosclerosis. If the present results are replicated, it may suggest that SLEs, depressive symptoms, and their interactive effect are not cardiotoxic among African American adults.Item Effects of Tobacco Components on Streptococcus mutans and the Role of S. mutans in Apoptotic Cell Death through Macrophage Interactions(Office of the Vice Chancellor for Research, 2014-04-11) Cavazos, Ana; Batarseh, Ghada; Windsor, L. Jack; Gregory, Richard L.Cigarettes have thousands of components aside from tobacco and nicotine that are harmful to the smoker’s body. Smoking is considered a significant risk factor for cardiovascular disease (CVD) and periodontal disease. One of the aims of this study is to determine the effect of different tobacco components on the growth of S. mutans. S. mutans is an oral bacteria found in most humans that is considered to be the causative agent for dental caries. S. mutans can potentially lead to the inflammation of the heart and arteries which can turn to atherosclerosis. Atherosclerosis is a complex inflammatory disease and is the leading cause of death in the United States. Inflammation is the main concern as it has a key role in the development of atherosclerosis. Irritation can be caused by the relationship of bacteria like S. mutans with macrophages and other white blood cells defending against foreign pathogens. The main focus of the research in this specific project is to establish how macrophage interactions with S. mutans are causing apoptosis in the endothelial cells lining the arteries and veins. Apoptosis is programmed, energy-dependent cell death that causes cells to shrink with no loss of the membrane integrity. The long term goal of this study is to determine if smokers are at higher risk of being diagnosed with atherosclerosis in correlation to S. mutans and tobacco components. Apoptosis is studied by the determination of apoptotic mediator levels. Apoptotic mediators allow for the measurement of cell death. This allows for the configuration of the data presented.Item The function of the 130kDa MLCK in regulating in vivo vascular permeability and angiogenesis(Office of the Vice Chancellor for Research, 2011-04-08) Chen, Meng; Herring, PaulDisruption of endothelial integrity is an essential component of vascular inflammation, angiogenesis, atherosclerosis, and tumor metastasis. Many studies have shown that activation of myosin light chain kinase (MLCK) in endothelial cell is correlated with increase in vascular permeability. Currently, most research in endothelial cells has focused on the 220kDa MLCK isoform which is the predominant isoform present in cultured endothelial cells. However, in freshly isolated uncultured endothelial cells, the 130kDa MLCK predominates. Yet nothing is known about the roles of the 130kDa MLCK isoform in endothelial cells. Therefore, our goal is to determine the role of the 130kDa MLCK in regulating vascular permeability and angiogenesis in vivo. To do this we will generate an endothelial cell-specific 130kDa MLCK knockout mice. As transcripts encoding the 130 and 220kDa MLCK isoforms are produced by independent promoters within the same mylk1 gene, I will selectively knockout the 130kDa MLCK by deleting unique cis-acting gene regulatory elements required for the expression of this transcript. A key element identified within the intron following the first exon of the 130kDa MLCK transcript has been flanked by LoxP sites such that Cre recombinase (Cre) mediated recombination will delete the element and attenuate expression of the 130kDa MLCK. By crossing these floxed mice with Tie2-Cre mice which express Cre specifically in endothelial cells, I will obtain endothelial cellspecific 130kDa MLCK knockout mice. In vivo vascular permeability and angiogenesis assays on these mice will allow me to determine the role played by the 130kDa MLCK in these processes. This study will not only help to identify specific functions of the 130kDa MLCK isoform, but also determine if this is a drug target for developing novel treatments of vascular diseases and cancer.Item INTERACTIONS OF HUMAN UMBILICAL VEIN ENDOTHELIAL CELLS WITH TOBACCO TREATED STREPTOCOCCUS MUTANS(Office of the Vice Chancellor for Research, 2013-04-05) Lanier, Branden; Windsor, L. Jack; Gregory, Richard L.Streptococcus mutans and tobacco are risk factors for atherosclerosis. The objective of this study was to determine the ability that a spaP isogenic defective mutant of S. mutans UA 159 has on binding to Human Umbilical Vein Endothelial Cells (HUVEC) when treated with tobacco products and what second messenger signals are involved. The study was conducted to examine the effects that various concentrations of cigarette smoke condensate (CSC)- and nicotine have on S. mutans cell cytotoxicity and expression of cytokines and growth factors from HUVECs. S. mutans was grown at 37°C and planktonic and biofilm cells were separated from the culture supernatant. The supernatant was discarded the cells were washed, sterilized with formaldehyde and washed again to remove the formaldehyde. The concentrations of the various S. mutans cells were standardized to the same concentration (absorbance of 0.50 ± 0.01) by spectroscopy at a wavelength of 600 nm. The lowest non-toxic levels of the sterilized bacterial cells were used to treat HUVECs for 72 hours and cytotoxicity was determined by lactate dehydrogenase (LDH) assays. The cytokine/growth factor expression will be determined by antibody protein arrays. The results are expected to indicate an increase in cytotoxicity with increasing cell concentrations, along with increased pro-inflammatory cytokine/growth factors expression by the HUVECs treated with tobacco treated S. mutans compared to S. mutans that was not treated with tobacco products. Second messenger signaling pathways will be analyzed with ERK and JNK inhibitors and specific antibodies to ERK and phospho-JNK. Immunoblots using HUVECs will be done to determine expression of ERK/JNK. A better understanding of the detrimental effects that tobacco has on the underlining causes of atherosclerosis can advance the quest of controlling the disease.Item Intracellular Ca2+ Dysregulation in Coronary Smooth Muscle Is Similar in Coronary Disease of Humans and Ossabaw Miniature Swine(Springer, 2022-02) Badin, Jill K.; Eggenberger, Caleb; Rodenbeck, Stacey Dineen; Hashmi, Zubair A.; Wang, I-wen; Garcia, Jose P.; Alloosh, Mouhamad; Sturek, Michael; Anatomy and Cell Biology, School of MedicineIntracellular free Ca2+ ([Ca2+]i) dysregulation occurs in coronary smooth muscle (CSM) in atherosclerotic coronary artery disease (CAD) of metabolic syndrome (MetS) swine. Our goal was to determine how CAD severity, arterial structure, and MetS risk factors associate with [Ca2+]i dysregulation in human CAD compared to changes in Ossabaw miniature swine. CSM cells were dispersed from coronary arteries of explanted hearts from transplant recipients and from lean and MetS swine with CAD. CSM [Ca2+]i elicited by Ca2+ influx and sarcoplasmic reticulum (SR) Ca2+ release and sequestration was measured with fura-2. Increased [Ca2+]i signaling was associated with advanced age and a greater media area in human CAD. Decreased [Ca2+]i signaling was associated with a greater number of risk factors and a higher plaque burden in human and swine CAD. Similar [Ca2+]i dysregulation exhibited in human and Ossabaw swine CSM provides strong evidence for the translational relevance of this large animal model.Item Long-term spironolactone treatment reduces coronary TRPC expression, vasoconstriction, and atherosclerosis in metabolic syndrome pigs(Springer, 2017) Li, Wennan; Chen, Xingjuan; Riley, Ashley M.; Hiett, S. Christopher; Temm, Constance J.; Beli, Eleni; Long, Xin; Chakraborty, Saikat; Alloosh, Mouhamad; White, Fletcher A.; Grant, Maria B.; Sturek, Michael; Obukhov, Alexander G.; Ophthalmology, School of MedicineCoronary transient receptor potential canonical (TRPC) channel expression is elevated in metabolic syndrome (MetS). However, differential contribution of TRPCs to coronary pathology in MetS is not fully elucidated. We investigated the roles of TRPC1 and TRPC6 isoforms in coronary arteries of MetS pigs and determined whether long-term treatment with a mineralocorticoid receptor inhibitor, spironolactone, attenuates coronary TRPC expression and associated dysfunctions. MetS coronary arteries exhibited significant atherosclerosis, endothelial dysfunction, and increased histamine-induced contractions. Immunohistochemical studies revealed that TRPC6 immunostaining was significantly greater in the medial layer of MetS pig coronary arteries compared to that in Lean pigs, whereas little TRPC6 immunostaining was found in atheromas. Conversely, TRPC1 immunostaining was weak in the medial layer but strong in MetS atheromas, where it was predominantly localized to macrophages. Spironolactone treatment significantly decreased coronary TRPC expression and dysfunctions in MetS pigs. In vivo targeted delivery of the dominant-negative (DN)-TRPC6 cDNA to the coronary wall reduced histamine-induced calcium transients in the MetS coronary artery medial layer, implying a role for TRPC6 in mediating calcium influx in MetS coronary smooth muscles. Monocyte adhesion was increased in Lean pig coronary arteries cultured in the presence of aldosterone; and spironolactone antagonized this effect, suggesting that coronary mineralocorticoid receptor activation may regulate macrophage infiltration. TRPC1 expression in atheroma macrophages was associated with advanced atherosclerosis, whereas medial TRPC6 upregulation correlated with increased histamine-induced calcium transients and coronary contractility. We propose that long-term spironolactone treatment may be a therapeutic strategy to decrease TRPC expression and coronary pathology associated with MetS.Item Mechanisms of Attachment of Tobacco-Treated Streptococcus mutans to Human Endothelial Cells(Office of the Vice Chancellor for Research, 2013-04-05) Miller, Alyssa R.Smoking has been proven to cause increased dental caries, which is an infectious disease caused by Streptococcus mutans, a gram-positive bacteria commonly found in the oral cavity. S. mutans is also known for its contribution to atherosclerosis, specifically the accumulation of plaque in the coronary arteries. This is facilitated by the interaction and binding of S. mutans to local endothelial cells (HUVEC). This study was conducted to explore the direct effects that tobacco has on the ability of S. mutans to affect endothelial cells that might lead to atherosclerosis. S. mutans were treated with different concentrations of nicotine and cigarette smoke condensate (CSC) to test if they affect the binding capabilities of S. mutans to endothelial cells. Blocking reagents, enolase antibody and purified DnaK, were also used to treat the HUVEC to observe the effects these reagents have on the ability of S. mutans to bind to the cells. Binding was measured by preforming a binding assay that incorporated these reagents and reading the absorbance using a spectrophotometer at 450 nm. To do this, sonicated HUVEC were added to a 96-well microtiter plate with 1% bovine serum albumin (BSA), followed by treated S. mutans, extra-avidin labeled horseradish peroxidase, and O-phenylenediamine (OPD). The experiment is still in progress; therefore, no results have been obtained thus far. However, it is expected that the nicotine/CSC treatment of S. mutans will increase binding to the endothelial cells thereby providing a possible mechanism of S. mutans contributing to atherosclerosis. The knowledge obtained from this experiment will be significant in developing treatment modalities to decrease the effects of smoking on cardiovascular disease.Item Nicotine Effects Surface Bound Enolase on Streptococcus mutans and Its Binding to Human Plasminogen(Office of the Vice Chancellor for Research, 2013-04-05) Walters, Kamilah; Gregory, Richard L.Streptococcus mutans is the major bacterial agent responsible for dental caries. Previous research has shown that smokers have increased caries and that nicotine increases biofilm formation of S. mutans. S. mutans is also associated with atherosclerosis, another disease commonly found in smokers. However, little research has been done to investigate the direct effect of nicotine on the ability of S. mutans to bind to endothelial cells and lead to atherosclerosis. The two objectives of this study were to determine how nicotine affects the level of enolase, a glycolytic enzyme, on the surface of S. mutans, and next to determine its effect on binding of treated bacteria to human plasminogen, a protein present in the bloodstream. S. mutans strain UA159 was grown overnight in tryptic soy broth treated with 0, 0.5, 1, and 2 mg/mL nicotine at 37◦C in 5% CO2. These cells were used to coat a microtiter plate, and various levels of surface bound enolase and binding to plasminogen were determined using enzyme-linked immunosorbent assays (ELISA). A preliminary trial showed increase in both surface bound enolase and binding to plasminogen with increasing nicotine concentration. Similar results are to be expected with repetition of this procedure, indicating that nicotine up-regulates the bacterial expression of enolase and its binding to plasminogen, probably through plasminogen binding receptors, contributing to the virulence of S. mutans. Knowledge of the attachment mechanisms of S. mutans in the presence of tobacco may aid in prevention of tobacco-related atherosclerosis.