Circulatory and Respiratory Physiology Commons^™

Angiotensinogen In Sex And Hypertension: New Insights From The Multi-Ethnic Study Of Atherosclerosis (Mesa), Alan Daugherty, Hong S. Lu, George L. Bakris

Saha Cardiovascular Research Center Faculty Publications

No abstract provided.

Chronic Environmental Circadian Disruption Increases Atherosclerosis And Dyslipidemia In Female, But Not Male, Apolipoproteine-Deficient Mice, Jeffrey M. Chalfant, Deborah A. Howatt, Victoria B. Johnson, Lisa R. Tannock, Alan Daugherty, Julie S. Pendergast

Saha Cardiovascular Research Center Faculty Publications

Shift work chronically disrupts circadian rhythms and increases the risk of developing cardiovascular disease. However, the mechanisms linking shift work and cardiovascular disease are largely unknown. The goal of this study was to investigate the effects of chronically shifting the light-dark (LD) cycle, which models the disordered exposure to light that may occur during shift work, on atherosclerosis. Atherosclerosis is the progressive accumulation of lipid-filled lesions within the artery wall and is the leading cause of cardiovascular disease. We studied ApolipoproteinE-deficient (ApoE−/−) mice that are a well-established model of atherosclerosis. Male and female ApoE−/− mice were housed in control 12L:12D …

Cervical Spinal Cord Injury Leads To Injury And Altered Metabolism In The Lungs, Emily E. Huffman, Brittany E. Dong, Harrison A. Clarke, Lyndsay E. A. Young, Matthew S. Gentry, Derek B. Allison, Ramon C. Sun, Christopher M. Waters, Warren J. Alilain

Saha Cardiovascular Research Center Faculty Publications

High-cervical spinal cord injury often disrupts respiratory motor pathways and disables breathing in the affected population. Moreover, cervically injured individuals are at risk for developing acute lung injury, which predicts substantial mortality rates. While the correlation between acute lung injury and spinal cord injury has been found in the clinical setting, the field lacks an animal model to interrogate the fundamental biology of this relationship. To begin to address this gap in knowledge, we performed an experimental cervical spinal cord injury (N = 18) alongside sham injury (N = 3) and naïve animals (N = 15) to assess lung injury …

Ferric Chloride-Induced Arterial Thrombosis And Sample Collection For 3d Electron Microscopy Analysis, Smita Joshi, Alexis N. Smith, Kanakanagavalli Shravani Prakhya, Hammodah Rawhi Hammodah Alfar, Joshua Lykins, Ming Zhang, Irina D. Pokrovskaya, Maria A. Aronova, Richard D. Leapman, Brian Storrie, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Cardiovascular diseases are a leading cause of mortality and morbidity worldwide. Aberrant thrombosis is a common feature of systemic conditions like diabetes and obesity, and chronic inflammatory diseases like atherosclerosis, cancer, and autoimmune diseases. Upon vascular injury, usually the coagulation system, platelets, and endothelium act in an orchestrated manner to prevent bleeding by forming a clot at the site of the injury. Abnormalities in this process lead to either excessive bleeding or uncontrolled thrombosis/insufficient antithrombotic activity, which translates into vessel occlusion and its sequelae. The FeCl3-induced carotid injury model is a valuable tool in probing how thrombosis initiates and progresses …

Novel Smad3 Variant Identified In A Patient With Familial Aortopathy Modeled Using A Zebrafish Embryo Assay, Mary Burchett Sheppard, Jeffrey D. Smith, Lisa L. Bergmann, Jakub Konrad Famulski

Saha Cardiovascular Research Center Faculty Publications

In human, pathogenic variants in smad3 are one cause of familial aortopathy. We describe a novel SMAD3 variant of unknown significance (VUS), V244F, in a patient who presented with aortic root dilation, right coronary artery ectasia, abdominal aortic aneurysm, right vertebral artery atresia, and cavernoma. Determination of variant pathogenicity impacted multiple aspects of the patient’s care, including the most appropriate surgical threshold for which to recommend a valve-sparing aortic root replacement. To determine whether the newly identified SMAD3 variant, and whether SMAD3 induced aortopathy in general, can be assayed in a zebrafish embryo model, we injected smad3a mRNA into Tg[kdrl:mCherry] …

Aortic Stress Activates An Adaptive Program In Thoracic Aortic Smooth Muscle Cells That Maintains Aortic Strength And Protects Against Aneurysm And Dissection In Mice, Chen Zhang, Yanming Li, Abhijit Chakraborty, Yang Li, Kimberly R. Rebello, Pingping Ren, Wei Luo, Lin Zhang, Hong S. Lu, Lisa A. Cassis, Joseph S. Coselli, Alan Daugherty, Scott A. Lemaire, Ying H. Shen

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: When aortic cells are under stress, such as increased hemodynamic pressure, they adapt to the environment by modifying their functions, allowing the aorta to maintain its strength. To understand the regulation of this adaptive response, we examined transcriptomic and epigenomic programs in aortic smooth muscle cells (SMCs) during the adaptive response to AngII (angiotensin II) infusion and determined its importance in protecting against aortic aneurysm and dissection (AAD).

METHODS: We performed single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq) analyses in a mouse model of sporadic AAD induced by AngII infusion. We also examined the direct …

Gasdermin D Deficiency In Vascular Smooth Muscle Cells Ameliorates Abdominal Aortic Aneurysm Through Reducing Putrescine Synthesis, Jianing Gao, Yanghui Chen, Huiqing Wang, Xin Li, Ke Li, Yangkai Xu, Xianwei Xie, Yansong Guo, Nana Yang, Xinhua Zhang, Dong Ma, Hong S. Lu, Ying H. Shen, Yong Liu, Jifeng Zhang, Y. Eugene Chen, Alan Daugherty, Dao Wen Wang, Lemin Zheng

Saha Cardiovascular Research Center Faculty Publications

Abdominal aortic aneurysm (AAA) is a common vascular disease associated with significant phenotypic alterations in vascular smooth muscle cells (VSMCs). Gasdermin D (GSDMD) is a pore-forming effector of pyroptosis. In this study, the role of VSMC-specific GSDMD in the phenotypic alteration of VSMCs and AAA formation is determined. Single-cell transcriptome analyses reveal Gsdmd upregulation in aortic VSMCs in angiotensin (Ang) II-induced AAA. VSMC-specific Gsdmd deletion ameliorates Ang II-induced AAA in apolipoprotein E (ApoE)−/− mice. Using untargeted metabolomic analysis, it is found that putrescine is significantly reduced in the plasma and aortic tissues of VSMC-specific GSDMD deficient mice. High putrescine levels …

The Mechanism And Therapy Of Aortic Aneurysms, Jianing Gao, Huanhuan Cao, Gaofei Hu, Yufei Wu, Yangkai Xu, Hongtu Cui, Hong S. Lu, Lemin Zheng

Saha Cardiovascular Research Center Faculty Publications

Aortic aneurysm is a chronic aortic disease affected by many factors. Although it is generally asymptomatic, it poses a significant threat to human life due to a high risk of rupture. Because of its strong concealment, it is difficult to diagnose the disease in the early stage. At present, there are no effective drugs for the treatment of aneurysms. Surgical intervention and endovascular treatment are the only therapies. Although current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm, the specific mechanisms remain unclear. Researchers are further exploring the pathogenesis …

Association Of Notch3 With Elastic Fiber Dispersion In The Infrarenal Abdominal Aorta Of Cynomolgus Monkeys, Sohei Ito, Naofumi Amioka, Michael K. Franklin, Pengjun Wang, Ching-Ling Liang, Yuriko Katsumata, Lei Cai, Ryan E. Temel, Alan Daugherty, Hong S. Lu, Hisashi Sawada

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: The regional heterogeneity of vascular components and transcriptomes is an important determinant of aortic biology. This notion has been explored in multiple mouse studies. In the present study, we examined the regional heterogeneity of aortas in nonhuman primates.

METHODS: Aortic samples were harvested from the ascending, descending thoracic, suprarenal, and infrarenal regions of young control monkeys and adult monkeys with high fructose consumption for 3 years. The regional heterogeneity of aortic structure and transcriptomes was examined by histological and bulk RNA sequencing analyses, respectively.

RESULTS: Immunostaining of CD31 and αSMA (alpha-smooth muscle actin) revealed that endothelial and smooth muscle …

Predictors And Outcomes Of Acute Pulmonary Embolism In Covid-19; Insights From Us National Covid Cohort Collaborative, Muhammad H. Gul, Zin Mar Htun, Vinicio De Jesus Perez, Muhammad Suleman, Samiullah Arshad, Muhammad Imran, Mahender Vyasabattu, Jeremy P. Wood, Michael I. Anstead, Peter E. Morris

Saha Cardiovascular Research Center Faculty Publications

Objectives To investigate whether COVID-19 patients with pulmonary embolism had higher mortality and assess the utility of d-dimer in predicting acute pulmonary embolism.

Patients and methods Using the National Collaborative COVID-19 retrospective cohort, a cohort of hospitalized COVID-19 patients was studied to compare 90-day mortality and intubation outcomes in patients with and without pulmonary embolism in a multivariable cox regression analysis. The secondary measured outcomes in 1:4 propensity score-matched analysis included length of stay, chest pain incidence, heart rate, history of pulmonary embolism or DVT, and admission laboratory parameters.

Results Among 31,500 hospitalized COVID-19 patients, 1117 (3.5%) patients were diagnosed …

Relative Adrenal Insufficiency Is A Risk Factor And Endotype Of Sepsis - A Proof-Of- Concept Study To Support A Precision Medicine Approach To Guide Glucocorticoid Therapy For Sepsis, Chia-Hua Wu, Ling Guo, Dan Hao, Qian Wang, Xiang Ye, Misa Ito, Bin Huang, Chieko Mineo, Philip W. Shaul, Xiang-An Li

Saha Cardiovascular Research Center Faculty Publications

Introduction: 25-60% of septic patients experience relative adrenal insufficiency (RAI) and glucocorticoid (GC) is frequently used in septic patients. However, the efficacy of GC therapy and whether GC therapy should be based on the status of RAI are highly controversial. Our poor understanding about the pathogenesis of RAI and a lack of RAI animal model present significant barriers to address these critical issues.

Methods: Scavenger receptor BI (SR-BI) regulates stress-induced GC (iGC) production in response to stress. We generated SF1CreSR-BIfl/fl mice and utilized the mice as a RAI model to elucidate the pathogenesis of RAI and GC therapy in sepsis. …

Manipulation Of Components Of The Renin Angiotensin System In Renal Proximal Tubules Fails To Alter Atherosclerosis In Hypercholesterolemic Mice, Masayoshi Kukida, Naofumi Amioka, Dien Ye, Hui Chen, Jessica J. Moorleghen, Ching-Ling Liang, Deborah A. Howatt, Yuriko Katsumata, Motoko Yanagita, Hisashi Sawada, Alan Daugherty, Hong S. Lu

Saha Cardiovascular Research Center Faculty Publications

Background and objective: Whole body manipulation of the renin-angiotensin system (RAS) consistently exerts profound effects on experimental atherosclerosis development. A deficit in the literature has been a lack of attention to the effects of sex. Also, based on data with gene-deleted mice, the site of RAS activity that influences lesion formation is at an unknown distant location. Since angiotensin (AngII) concentrations are high in kidney and the major components of the RAS are present in renal proximal tubule cells (PTCs), this study evaluated the role of the RAS in PTCs in atherosclerosis development.

Methods and results: Mice with an LDL …

Cd47 Antisense Oligonucleotide Treatment Attenuates Obesity And Its-Associated Metabolic Dysfunction, Taesik Gwag, Dong Li, Eric Ma, Zhenheng Guo, Ying Liang, Shuxia Wang

Saha Cardiovascular Research Center Faculty Publications

Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its‑associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six‑week old ob/ob mice …

Platelet Glycogenolysis Is Important For Energy Production And Function, Kanakanagavalli Shravani Prakhya, Hemendra J. Vekaria, Daniёlle M. Coenen, Linda Omali, Joshua Lykins, Smita Joshi, Hammodah Rawhi Hammodah Alfar, Qing Jun Wang, Patrick G. Sullivan, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Although the presence of glycogen in platelets was established in the 1960s, its importance to specific functions (i.e., activation, secretion, aggregation, and clot contraction) remains unclear. Patients with glycogen storage disease often present with increased bleeding and glycogen phosphorylase (GP) inhibitors, when used as treatments for diabetes, induce bleeding in preclinical studies suggesting some role for this form of glucose in hemostasis. In the present work, we examined how glycogen mobilization affects platelet function using GP inhibitors (CP316819 and CP91149) and a battery of ex vivo assays. Blocking GP activity increased glycogen levels in resting and thrombin-activated platelets and inhibited …

The Complementary Roles Of Vamp-2, -3, And -7 In Platelet Secretion And Function, Smita Joshi, Kanakanagavalli Shravani Prakhya, Alexis N. Smith, Harry Chanzu, Ming Zhang, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Platelet secretion requires Soluble N-ethylmaleimide Sensitive Attachment Protein Receptors (SNAREs). Vesicle SNAREs/Vesicle-Associated Membrane Proteins (v-SNAREs/ VAMPs) on granules and t-SNAREs in plasma membranes mediate granule release. Platelet VAMP heterogeneity has complicated the assessment of how/if each is used and affects hemostasis. To address the importance of VAMP-7 (V7), we analyzed mice with global deletions of V3 and V7 together or platelet-specific deletions of V2, V3, and global deletion of V7. We measured the kinetics of cargo release, and its effects on three injury models to define the context-specific roles of these VAMPs. Loss of V7 minimally affected dense and α …

Best3-Mediated Mekk2/3 Activation: A Novel Therapeutic Target In Aortopathies, Tatiana Zyrianova, Benjamin Lopez, Kathlyn Zou, Charles Gu, Dayna Pham, Sriharsha Talapaneni, Christopher M. Waters, Riccardo Olcese, Andreas Schwingshackl

Saha Cardiovascular Research Center Faculty Publications

Influenza-A virus (IAV) infects yearly an estimated one billion people worldwide, resulting in 300,000–650,000 deaths. Preventive vaccination programs and antiviral medications represent the mainstay of therapy, but with unacceptably high morbidity and mortality rates, new targeted therapeutic approaches are urgently needed. Since inflammatory processes are commonly associated with measurable changes in the cell membrane potential (Em), we investigated whether Em hyperpolarization via TREK-1 (K2P 2.1) K þ channel activation can protect against influenza-A virus (IAV)-induced pneumonia. We infected mice with IAV, which after 5 days caused 10–15% weight loss and a decrease in spontaneous activity, representing a clinically relevant infection. …

Deep Learning, 3d Ultrastructural Analysis Reveals Quantitative Differences In Platelet And Organelle Packing In Covid-19/Sarscov2 Patient-Derived Platelets, Sagar S. Matharu, Cassidy S. Nordmann, Kurtis R. Ottman, Rahul Akkem, Douglas Palumbo, Denzel R. D. Cruz, Kenneth Campbell, Gail Sievert, Jamie L. Sturgill, James Zachary Porterfield, Smita Joshi, Hammodah Rawhi Hammodah Alfar, Chi Peng, Irina D. Pokrovskaya, Jeffrey A. Kamykowski, Jeremy P. Wood, Beth A. Garvy, Maria A. Aronova, Sidney W. Whiteheart, Richard D. Leapman, Brian Storrie

Saha Cardiovascular Research Center Faculty Publications

Platelets contribute to COVID-19 clinical manifestations, of which microclotting in the pulmonary vasculature has been a prominent symptom. To investigate the potential diagnostic contributions of overall platelet morphology and their α-granules and mitochondria to the understanding of platelet hyperactivation and micro-clotting, we undertook a 3D ultrastructural approach. Because differences might be small, we used the high-contrast, high-resolution technique of focused ion beam scanning EM (FIB-SEM) and employed deep learning computational methods to evaluate nearly 600 individual platelets and 30 000 included organelles within three healthy controls and three severely ill COVID-19 patients. Statistical analysis reveals that the α-granule/ mitochondrion-to-plateletvolume ratio …

Lrp1 Protects Against Excessive Superior Mesenteric Artery Remodeling By Modulating Angiotensin Ii–Mediated Signaling, Jackie M. Zhang, Dianaly T. Au, Hisashi Sawada, Michael K. Franklin, Jessica J. Moorleghen, Deborah A. Howatt, Pengjun Wang, Brittany O. Aicher, Brian Hampton, Mary Migliorini, Fenge Ni, Adam E. Mullick, Mashhood M. Wani, Areck A. Ucuzian, Hong S. Lu, Selen C. Muratoglu, Alan Daugherty, Dudley K. Strickland

Saha Cardiovascular Research Center Faculty Publications

Vascular smooth muscle cells (vSMCs) exert a critical role in sensing and maintaining vascular integrity. These cells abundantly express the low-density lipoprotein receptor–related protein 1 (LRP1), a large endocytic signaling receptor that recognizes numerous ligands, including apolipoprotein E–rich lipoproteins, proteases, and protease-inhibitor complexes. We observed the spontaneous formation of aneurysms in the superior mesenteric artery (SMA) of both male and female mice in which LRP1 was genetically deleted in vSMCs (smLRP1–/– mice). Quantitative proteomics revealed elevated abundance of several proteins in smLRP1–/– mice that are known to be induced by angiotensin II–mediated (AngII-mediated) signaling, suggesting that this pathway was dysregulated. …

Macrophage Angiotensin-Converting Enzyme Reduces Atherosclerosis By Increasing Peroxisome Proliferator-Activated Receptor Α And Fundamentally Changing Lipid Metabolism, Duoyao Cao, Zakir Khan, Xiaomo Li, Suguru Saito, Ellen A. Bernstein, Aaron R. Victor, Faizan Ahmed, Aoi O. Hoshi, Luciana C. Veiras, Tomohiro Shibata, Mingtian Che, Lei Cai, Michifumi Yamashita, Ryan E. Temel, Jorge F. Giani, Daniel J. Luthringer, Ajit S. Divakaruni, Derick Okwan-Duodu, Kenneth E. Bernstein

Saha Cardiovascular Research Center Faculty Publications

Aims The metabolic failure of macrophages to adequately process lipid is central to the aetiology of atherosclerosis. Here, we examine the role of macrophage angiotensin-converting enzyme (ACE) in a mouse model of PCSK9-induced atherosclerosis.

Methods and results Atherosclerosis in mice was induced with AAV-PCSK9 and a high-fat diet. Animals with increased macrophage ACE (ACE 10/10 mice) have a marked reduction in atherosclerosis vs. WT mice. Macrophages from both the aorta and peritoneum of ACE 10/10 express increased PPARα and have a profoundly altered phenotype to process lipids characterized by higher levels of the surface scavenger receptor CD36, increased uptake of …

Imaging Techniques For Aortic Aneurysms And Dissections In Mice: Comparisons Of Ex Vivo, In Situ, And Ultrasound Approaches, Sohei Ito, Hong S. Lu, Alan Daugherty, Hisashi Sawada

Saha Cardiovascular Research Center Faculty Publications

Aortic aneurysms and dissections are life-threatening conditions that have a high risk for lethal bleeding and organ malperfusion. Many studies have investigated the molecular basis of these diseases using mouse models. In mice, ex vivo, in situ, and ultrasound imaging are major approaches to evaluate aortic diameters, a common parameter to determine the severity of aortic aneurysms. However, accurate evaluations of aortic dimensions by these imaging approaches could be challenging due to pathological features of aortic aneurysms. Currently, there is no standardized mode to assess aortic dissections in mice. It is important to understand the characteristics of each approach for …

No Effect Of Hypercholesterolemia On Elastase-Induced Experimental Abdominal Aortic Aneurysm Progression, Toru Ikezoe, Takahiro Shoji, Jia Guo, Fanru Shen, Hong S. Lu, Alan Daugherty, Masao Nunokawa, Hiroshi Kubota, Masaaki Miyata, Baohui Xu, Ronald L. Dalman

Saha Cardiovascular Research Center Faculty Publications

Objective: Epidemiological studies link hyperlipidemia with increased risk for abdominal aortic aneurysms (AAAs). However, the influence of lipid-lowering drugs statins on prevalence and progression of clinical and experimental AAAs varies between reports, engendering controversy on the association of hyperlipidemia with AAA disease. This study investigated the impact of hypercholesterolemia on elastase-induced experimental AAAs in mice. Methods: Both spontaneous (targeted deletion of apolipoprotein E) and induced mouse hypercholesterolemia models were employed. In male wild type (WT) C57BL/6J mice, hypercholesterolemia was induced via intraperitoneal injection of an adeno-associated virus (AAV) encoding a gain-of-function proprotein convertase subtilisin/kexin type 9 mutation (PCSK9) followed by …

Effect Of Metformin On The High-Density Lipoprotein Proteome In Youth With Type 1 Diabetes, Evgenia Gourgari, Kristen J. Nadeau, Laura Pyle, Martin P. Playford, Junfeng Ma, Nehal N. Mehta, Alan T. Remaley, Scott M. Gordon

Saha Cardiovascular Research Center Faculty Publications

Background: Youth with type 1 diabetes (T1D) have normal or elevated High-Density Lipoprotein Cholesterol (HDL-C), however, the function of HDL, partly mediated by the HDL proteome, may be impaired. Metformin can be used as an adjunct therapy in youth with T1D, but its effects on the HDL proteome are unknown.

Objective: To determine the effect of metformin on the HDL proteome.

Subjects: Youth (12-20 years old) with T1D who had a BMI > 90th percentile, HbA1c > 8.0% and Tanner stage 5.

Methods: Double-blinded, placebo-controlled randomized sub-study. We examined the effects of metformin (n = 25) or placebo (n = …

Effects Of Endogenous Angiotensin Ii On Abdominal Aortic Aneurysms And Atherosclerosis In Angiotensin Ii-Infused Mice, Masayoshi Kukida, Hisashi Sawada, Satoko Ohno-Urabe, Deborah A. Howatt, Jessica J. Moorleghen, Marko Poglitsch, Alan Daugherty, Hong S. Lu

Saha Cardiovascular Research Center Faculty Publications

No abstract provided.

Effect Of Niacin Monotherapy On High Density Lipoprotein Composition And Function, Scott M. Gordon, Marcelo J. Amar, Kianoush Jeiran, Michael Stagliano, Emma Staller, Martin P. Playford, Nehal N. Mehta, Tomas Vaisar, Alan T. Remaley

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: Niacin has modest but overall favorable effects on plasma lipids by increasing high density lipoprotein cholesterol (HDL-C) and lowering triglycerides. Clinical trials, however, evaluating niacin therapy for prevention of cardiovascular outcomes have returned mixed results. Recent evidence suggests that the HDL proteome may be a better indicator of HDL's cardioprotective function than HDL-C. The objective of this study was to evaluate the effect of niacin monotherapy on HDL protein composition and function.

METHODS: A 20-week investigational study was performed with 11 participants receiving extended-release niacin (target dose = 2 g/day) for 16-weeks followed by a 4-week washout period. HDL …

Hdl Subclass Proteomic Analysis And Functional Implication Of Protein Dynamic Change During Hdl Maturation, Yuling Zhang, Scott M. Gordon, Hang Xi, Seungbum Choi, Merlin Abner Paz, Runlu Sun, William Yang, Jason Saredy, Mohsin Khan, Alan Thomas Remaley, Jing-Feng Wang, Xiaofeng Yang, Hong Wang

Saha Cardiovascular Research Center Faculty Publications

Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven …

Proteomic Alterations Of Hdl In Youth With Type 1 Diabetes And Their Associations With Glycemic Control: A Case-Control Study, Evgenia Gourgari, Junfeng Ma, Martin P. Playford, Nehal N. Mehta, Radoslav Goldman, Alan T. Remaley, Scott M. Gordon

Saha Cardiovascular Research Center Faculty Publications

Background: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.

Methods: This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and …

Chronic Low Intensity Continuous And Interval Training Prevent Heart Failure-Related Coronary Artery Stiffness, An Ouyang

Theses and Dissertations--Kinesiology and Health Promotion

Heart failure (HF) induced by aortic pressure over-load is associated with increased coronary artery stiffness. Perivascular adipose tissue (PVAT) and advanced glycation end products (AGE) both promote arterial stiffness. However, the mechanisms by which coronary PVAT promotes arterial stiffness and the efficacy of exercise to prevent coronary stiffness are unknown. The present study hypothesized both chronic continuous and interval exercise training would prevent coronary artery stiffness associated with inhibition of PVAT secreted AGE. Yucatan mininature swine were divided into four groups: control-sedentary (CON), aortic-banded sedentary heart failure (HF), aortic-banded HF continuous exercise trained (HF+CONT), and aortic-banded HF interval exercise trained …

Platelet Cd36 Signaling Through Erk5 Promotes Caspase-Dependent Procoagulant Activity And Fibrin Deposition In Vivo, Moua Yang, Andaleb Kholmukhamedov, Marie L. Schulte, Brian C. Cooley, Na'il O. Scoggins, Jeremy P. Wood, Scott J. Cameron, Craig N. Morrell, Shawn M. Jobe, Roy L. Silverstein

Saha Cardiovascular Research Center Faculty Publications

Dyslipidemia is a risk factor for clinically significant thrombotic events. In this condition, scavenger receptor CD36 potentiates platelet reactivity through recognition of circulating oxidized lipids. CD36 promotes thrombosis by activating redox-sensitive signaling molecules, such as the MAPK extracellular signal-regulated kinase 5 (ERK5). However, the events downstream of platelet ERK5 are not clear. In this study, we report that oxidized low-density lipoprotein (oxLDL) promotes exposure of procoagulant phosphatidylserine (PSer) on platelet surfaces. Studies using pharmacologic inhibitors indicate that oxLDL-CD36 interaction–induced PSer exposure requires apoptotic caspases in addition to the downstream CD36-signaling molecules Src kinases, hydrogen peroxide, and ERK5. Caspases promote PSer …

Acute Pressor Response To Psychosocial Stress Is Dependent On Endothelium‐Derived Endothelin‐1, Brandon M. Fox, Bryan K. Becker, Analia S. Loria, Kelly A. Hyndman, Chunhua Jin, Hannah Clark, Robin Johns, Masashi Yanagisawa, David M. Pollock, Jennifer S. Pollock

Pharmacology and Nutritional Sciences Faculty Publications

Background

Acute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.

Methods and Results

Adult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in …

Influence Of Longitudinal Position On The Evolution Of Steady-State Signal In Cardiac Cine Balanced Steady-State Free Precession Imaging, Tyler J. Spear, Tori A. Stromp, Steve W. Leung, Moriel H. Vandsburger

Saha Cardiovascular Research Center Faculty Publications

Background: Emerging quantitative cardiac magnetic resonance imaging (CMRI) techniques use cine balanced steady-state free precession (bSSFP) to measure myocardial signal intensity and probe underlying physiological parameters. This correlation assumes that steady-state is maintained uniformly throughout the heart in space and time.

Purpose: To determine the effects of longitudinal cardiac motion and initial slice position on signal deviation in cine bSSFP imaging by comparing two-dimensional (2D) and three-dimensional (3D) acquisitions.

Material and Methods: Nine healthy volunteers completed cardiac MRI on a 1.5-T scanner. Short axis images were taken at six slice locations using both 2D and 3D cine bSSFP. 3D acquisitions …