Cardiovascular Diseases Commons^™

Closing The Gaps In Care Of Dyslipidemia: Revolutionizing Management With Digital Health And Innovative Care Models, Samuel J. Apple, Rachel Clark, Jonathan Daich, Macarena Lopez Gonzalez, Robert J. Ostfeld, Peter P. Toth, Vera Bittner, Seth S. Martin, Jamal S. Rana, Salim S. Virani

Office of the Provost

Although great progress has been made in the diagnostic and treatment options for dyslipidemias, unawareness, underdiagnosis and undertreatment of these disorders remain a significant global health concern. Growth in digital applications and newer models of care provide novel tools to improve the management of chronic conditions such as dyslipidemia. In this review, we discuss the evolving landscape of lipid management in the 21st century, current treatment gaps and possible solutions through digital health and new models of care. Our discussion begins with the history and development of value-based care and the national establishment of quality metrics for various chronic conditions. …

Heartburn's Hidden Impact: A Narrative Review Exploring Gastroesophageal Reflux Disease (Gerd) As A Cardiovascular Disease Risk Factor, Jacob J. Gries, Bing Chen, Salim S. Virani, Hafeez Ul Hassan Virk, Hani Jneid, Chayakrit Krittanawong

Office of the Provost

Gastroesophageal reflux disease (GERD) is a very common disease with an estimated 442 million cases worldwide. It is a well-documented independent risk factor for many gastrointestinal pathologies, however, its role in cardiovascular disease (CVD) is unclear, despite its high prevalence in patients with CVD. Although traditionally considered a causative agent of noncardiac chest pain, a common imitator of cardiac chest pain, or an incidentally shared comorbidity in patients with CVD, a number of studies have implicated GERD and its therapies as risk factors for CVD. This narrative review will explore the relationship between GERD and CVD, including medical and mechanical …

Contemporary Homozygous Familial Hypercholesterolemia In The United States: Insights From The Cascade Fh Registry, Marina Cuchel, Paul C. Lee, Lisa C. Hudgins, P. Barton Duell, Zahid Ahmad, Seth J. Baum, Macrae F. Linton, Sarah D. De Ferranti, Christie M. Ballantyne, John A. Larry, Linda C. Hemphill, Iris Kindt, Samuel S. Gidding, Seth S. Martin, Patrick M. Moriarty, Paul P. Thompson, James A. Underberg, John R. Guyton, Rolf L. Andersen, David J. Whellan, Irwin Benuck, John P. Kane, Kelly Myers, William Howard, David Staszak, Allison Jamison, Mary C. Card, Mafalda Bourbon, Joana R. Chora, Daniel J. Rader, Joshua W. Knowles, Katherine Wilemon, Mary P. Mcgowan

Division of Cardiology Faculty Papers

Background

Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment‐resistant disorder characterized by early‐onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain.

Methods and Results

Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the …

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 …

Interactions Among Endothelial Nitric Oxide Synthase, Cardiovascular System, And Nociception During Physiological And Pathophysiological States, Niribili Sarmah, Andromeda M. Nauli, Ahmmed Ally, Surya M. Nauli

Pharmacy Faculty Articles and Research

Nitric oxide synthase (NOS) plays important roles within the cardiovascular system in physiological states as well as in pathophysiologic and specific cardiovascular (CV) disease states, such as hypertension (HTN), arteriosclerosis, and cerebrovascular accidents. This review discusses the roles of the endothelial NOS (eNOS) and its effect on cardiovascular responses that are induced by nociceptive stimuli. The roles of eNOS enzyme in modulating CV functions while experiencing pain will be discussed. Nociception, otherwise known as the subjective experience of pain through sensory receptors, termed “nociceptors”, can be stimulated by various external or internal stimuli. In turn, events of various cascade pathways …

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

Honors Program Projects

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, …

Nanoanalytical Analysis Of Bisphosphonate-Driven Alterations Of Microcalcifications Using A 3d Hydrogel System And In Vivo Mouse Model, Jessica L. Ruiz, Joshua D. Hutcheson, Luis Cardoso, Amirala Bakhshian Nik, Alexandra Condado De Abreu, Tan Pham, Fabrizio Buffolo, Sara Busatto, Stefania Frederici, Andrea Ridolfi, Masanori Aikawa, Sergio Bertazzo, Paolo Bergese, Sheldon Weinbaum, Elena Aikawa

Publications and Research

Vascular calcification predicts atherosclerotic plaque rupture and cardiovascular events. Retrospective studies of women taking bisphosphonates (BiPs), a proposed therapy for vascular calcification, showed that BiPs paradoxically increased morbidity in patients with prior acute cardiovascular events but decreased mortality in event-free patients. Calcifying extracellular vesicles (EVs), released by cells within atherosclerotic plaques, aggregate and nucleate calcification. We hypothesized that BiPs block EV aggregation and modify existing mineral growth, potentially altering microcalcification morphology and the risk of plaque rupture. Three-dimensional (3D) collagen hydrogels incubated with calcifying EVs were used to mimic fibrous cap calcification in vitro, while an ApoE−/− mouse was used …

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 …

Xx Sex Chromosome Complement Promotes Atherosclerosis In Mice, Yasir Alsiraj, Xuqi Chen, Sean E. Thatcher, Ryan E. Temel, Lei Cai, Eric M. Blalock, Wendy Katz, Heba M. Ali, Michael C. Petriello, Pan Deng, Andrew J. Morris, Xuping Wang, Aldons J. Lusis, Arthur P. Arnold, Karen Reue, Katherine L. Thompson, Patrick Tso, Lisa A. Cassis

Pharmacology and Nutritional Sciences Faculty Publications

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating …

The Roles Of Primary Cilia In Cardiovascular Diseases, Rajasekharreddy Pala, Maha Jamal, Qamar Alshammari, Surya M. Nauli

Pharmacy Faculty Articles and Research

Primary cilia are microtubule-based organelles found in most mammalian cell types. Cilia act as sensory organelles that transmit extracellular clues into intracellular signals for molecular and cellular responses. Biochemical and molecular defects in primary cilia are associated with a wide range of diseases, termed ciliopathies, with phenotypes ranging from polycystic kidney disease, liver disorders, mental retardation, and obesity to cardiovascular diseases. Primary cilia in vascular endothelia protrude into the lumen of blood vessels and function as molecular switches for calcium (Ca2+) and nitric oxide (NO) signaling. As mechanosensory organelles, endothelial cilia are involved in blood flow sensing. Dysfunction in endothelial …

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, …

Exposure To High Levels Of Noise Poses Hazards And Risks For Development Of Hypertension And Heart Disease: Potential Roles Of Unrecognized Ionized Hypomagnesemia And Release Of Ceramides And Platelet-Activating Factor, Burton M. Altura, Asefa Gebrewold, Anthony Carella, Nilank C. Shah, Bella T. Altura

Touro College of Osteopathic Medicine (Middletown) Publications and Research

It has been demonstrated in numerous human and animal studies that audiogenic stress (AS) can induce elevation of arterial blood pressure and cardiac damage and that noise –induced hearing loss may be associated with alterations in magnesium (Mg) metabolism. Our laboratories, over a period of approximately 40 years, have been investigating why AS causes high blood pressure and cardiac damage. This review focuses on a number of newer discoveries on why AS causes dysfunctions of the cardiovascular system (CVS) This review discusses the pivotal physiological and biochemical importance of Mg to body health and the fact that most Americans and …

The Association Between Type Of Fat And The Risk Of Developing Cardiovascular Diseases, Dovid Leib Glassner

The Science Journal of the Lander College of Arts and Sciences

Objective: To determine the significance of various types of dietary fat in the progression of atherosclerosis leading to heart disease. Methods: Study inclusion criteria constituted relevance to the discussion topic and peer reviewed literature. Age of the published material was taken into account as well, with greater preference being given to more recent research as the topic of nutrition and its relation to chronic disease remains an emerging science. Results: This research review found an overall significant relationship between the type (monounsaturated, polyunsaturated, saturated and trans-fat) of dietary fat intake and the incidence of cardiovascular disease. While earlier research identified …

Serum Tumor Necrosis Factor-Alpha Associates With Myocardial Oxygen Demand And Exercise Tolerance In Postmenopausal Women, Stephen J. Carter, David R. Bryan, William H. Neumeier, Stephen P. Glasser, Gary R. Hunter

Internal Medicine Faculty Publications

The functional implications of serum tumor necrosis factor-alpha (TNF-α), a marker of oxidative stress, on hemodynamic parameters at rest and during physical exertion are unclear. The aims of this investigation were to examine the independent associations of TNF-α on myocardial oxygen demand at rest and during submaximal exercise, while also evaluating the association of TNF-α on exercise tolerance. Forty, postmenopausal women, provided blood samples and completed a modified-Balke protocol to measure maximal oxygen uptake (VO_2max). Large artery compliance was measured by pulse contour analyses while rate-pressure product (RPP), an index of myocardial oxygen demand, was measured at rest …

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 …

Cruciferous And Allium Vegetable Intakes Are Inversely Associated With 15‐Year Atherosclerotic Vascular Disease Deaths In Older Adult Women, Lauren Blekkenhorst, Catherine P. Bondonno, Joshua Lewis, Amanda Devine, Kun Zhu, Wai Lim, Richard Woodman, Lawrence Beilin, Richard Prince, Jonathan M. Hodgson

Research outputs 2014 to 2021

Background

Higher vegetable intake is consistently associated with lower atherosclerotic vascular disease (ASVD) events. However, the components responsible and mechanisms involved are uncertain. Nonnutritive phytochemicals may be involved. The objective of this study was to investigate the associations of total vegetable intake and types of vegetables grouped according to phytochemical constituents with ASVD mortality.

Methods and Results

The cohort consisted of 1226 Australian women aged 70 years and older without clinical ASVD or diabetes mellitus at baseline (1998). Vegetable intakes were calculated per serving (75 g/d) and were also classified into prespecified types relating to phytochemical constituents. ASVD‐related deaths were …

Targeting Hepatic Heparin-Binding Egf-Like Growth Factor (Hb-Egf) Induces Anti-Hyperlipidemia Leading To Reduction Of Angiotensin Ii-Induced Aneurysm Development, Seonwook Kim, Lihua Yang, Seongu Kim, Richard G. Lee, Mark J. Graham, Judith A. Berliner, Aldons J. Lusis, Lei Cai, Ryan E. Temel, Debra L. Rateri, Sangderk Lee

Saha Cardiovascular Research Center Faculty Publications

Objective

The upregulated expression of heparin binding EGF-like growth factor (HB-EGF) in the vessel and circulation is associated with risk of cardiovascular disease. In this study, we tested the effects of HB-EGF targeting using HB-EGF-specific antisense oligonucleotide (ASO) on the development of aortic aneurysm in a mouse aneurysm model.

Approach and results

Low-density lipoprotein receptor (LDLR) deficient mice (male, 16 weeks of age) were injected with control and HB-EGF ASOs for 10 weeks. To induce aneurysm, the mice were fed a high fat diet (22% fat, 0.2% cholesterol; w/w) at 5 week point of ASO administration and infused with angiotensin …

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.

Population-Based Cohort Study In Outcome Of Phased Progression Of Atherosclerosis In China (Persuade): Objective, Rationale And Design, Dong-Kai Shan, Yong Zhou, You-Xin Wang, Xiang Gao, Wei Wang, Jun-Jie Yang, Yun-Dai Chen

Research outputs 2014 to 2021

The coronary artery calcification score and pericardial fat volume have recently been reported to be strongly associated with the severity and presence of coronary atherosclerosis. However, no studies have explored the outcome of phased progression of atherosclerosis by non-contrast computed tomography in asymptomatic people in China. The population-based cohort study in outcome of phased progression of atherosclerosis in China (PERSUADE), an observational, longitudinal and prospective cohort study in a target population of healthy subjects based in Jidong Oilfield (China), prospectively analyzes the outcome of phased progression of atherosclerosis by non-contrast computed tomography in healthy population. The results of this study …

Why Is Postoperative Atrial Fibrillation Difficult To Prevent And Treat: Potential Roles Of Unrecognized Magnesium Deficiency And Release Of Ceramide And Platelet-Activating Factor, Burton M. Altura, Nilank C. Shah, Gatha J. Shah, Jose Luis Perez-Albela, Bella T. Altura

Touro College of Osteopathic Medicine (Middletown) Publications and Research

Heart failure is a major cause of morbidity and mortality whose costs impose staggering health-care costs and often lengthy hospitalizations. Post-operative atrial fibrillation (POAF) represents a leading cause for heart failure, particularly after cardiac and lung surgeries. Although PAOF is a common cardiac arrhythmia, it is impossible to predict. As the worldwide population is aging, the incidence and prevalence of PAOF is growing. Identifying mechanisms for PAOF is attracting a considerable amount of research with no agreement on the mechanism(s). Our research on the heart and cardiovascular system, over the past 50-plus years, leads us to believe that major causes …

Insights Into The Possible Mechanisms By Which Platelet-Activating Factor And Paf-Receptors Function In Vascular Smooth Muscle In Magnesium Deficiency And Vascular Remodeling: Possible Links To Atherogenesis, Hypertension And Cardiac Failure, Burton M. Altura, Nilank C. Shah, Gatha J. Shah, Jose Luis Perez-Albela, Bella T. Altura

The School of Health Sciences Publications and Research

The authors discuss different studies concerning the relationship between platelet-activating factor (PAF) and PAF-receptors with atherosclerosis and hypertension.

Tuberculosis And Cardiovascular Disease: Linking The Epidemics, Moises A. Huaman, David Henson, Eduardo Ticona, Timothy R. Sterling, Beth A. Garvy

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The burden of tuberculosis and cardiovascular disease (CVD) is enormous worldwide. CVD rates are rapidly increasing in low- and middle-income countries. Public health programs have been challenged with the overlapping tuberculosis and CVD epidemics. Monocyte/macrophages, lymphocytes and cytokines involved in cellular mediated immune responses against Mycobacterium tuberculosis are also main drivers of atherogenesis, suggesting a potential pathogenic role of tuberculosis in CVD via mechanisms that have been described for other pathogens that establish chronic infection and latency. Studies have shown a pro-atherogenic effect of antibody-mediated responses against mycobacterial heat shock protein-65 through cross reaction with self-antigens in human vessels. Furthermore, …

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 …

Syndecan 4 Is Required For Endothelial Alignment In Flow And Atheroprotective Signaling, Nicolas Baeyens, Mary Jo Mulligan-Kehoe, Federico Corti, David D. Simon, Tyler D. Ross, John M. Rhodes, Thomas Z. Wang

Dartmouth Scholarship

Atherosclerotic plaque localization correlates with regions of disturbed flow in which endothelial cells (ECs) align poorly, whereas sustained laminar flow correlates with cell alignment in the direction of flow and resistance to atherosclerosis. We now report that in hypercholesterolemic mice, deletion of syndecan 4 (S4−/−) drastically increased atherosclerotic plaque burden with the appearance of plaque in normally resistant locations. Strikingly, ECs from the thoracic aortas of S4−/− mice were poorly aligned in the direction of the flow. Depletion of S4 in human umbilical vein endothelial cells (HUVECs) using shRNA also inhibited flow-induced alignment in vitro, which was rescued by re-expression …