Circulatory and Respiratory Physiology Commons^™

Animal Models Of Aortic Aneurysm And Dissection: A Comparative Guide For Mechanism, Therapeutic Testing, And Translational Readouts, Shayan Mohammadmoradi, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Aortic aneurysms and dissections are devastating vascular diseases with high mortality, yet no pharmacological therapy has proven effective in halting growth or preventing rupture. Surgical and endovascular repair remain the only treatment options for advanced disease. Animal models have been indispensable in defining mechanisms and testing candidate therapies, but the diversity of protocols, strain-dependent variability, and heterogeneous endpoints complicate interpretation and translation. This review provides an update focused on how to match models to specific research questions. We critically compare commonly used abdominal aortic aneurysm (AAA) models (angiotensin II ± hyperlipidemia, elastase, calcium chloride, β-aminopropionitrile BAPN hybrids, and mineralocorticoid agonist/fludrocortisone …

Leveraging Clinical Standards To Improve The Translational Relevance Of Therapies For Experimental Spinal Cord Injury, Aaron L. Silverstein

Theses and Dissertations--Neuroscience

Efforts to improve treatment of spinal cord injury (SCI) often use animals to develop effective therapeutics, intending to improve the survival and the quality of life of persons with SCI. Over half of all SCIs in the United States occur at the cervical level and often cause locomotor deficits and life-threatening breathing dysfunction. Thus, my dissertation is focused on this important patient population.

After beginning with a description of translational research and surveying SCI from a clinical standpoint, I turned to describe experimental models of cervical SCI and more detailed neuroimmunological findings relevant to my work. Then, I conducted a …

Biochemical And Biophysical Properties Of Failing Myocardium In Rare Patient Populations, Gregory Nathaniel Milburn

Theses and Dissertations--Physiology

Heart failure has diverse underlying etiologies, complicating research. While some types, like ischemic disease or inherited mutations, are well-studied, research on rarer forms has lagged. Understanding the molecular drivers in these populations may enhance diagnostics and therapies. This work examines two rare groups: patients with ATTR cardiac amyloidosis and those receiving mechanical assist device support. We show that myocardium from patients with amyloidosis has increased fibrosis and reduced force production without changes in cross-bridge kinetics. Additionally, we show that the passive stiffness of amyloidosis myocardium is not different from non-failing myocardium, indicating increased ventricular wall thickness may cause restrictive filling. …

Serglycin Controls Megakaryocyte Retention Of Platelet Factor 4 And Influences Megakaryocyte Fate In Bone Marrow, Joshua Lykins, Isabelle C. Becker, Virginia Camacho, Hammodah Rawhi Hammodah Alfar, Joonwoo Park, Joseph Italiano, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Megakaryocytes (MKs) produce platelets, and similar to other hematopoietic progenitors, they are involved in homeostatic aspects of their bone marrow niche. MKs release and endocytose various factors, such as platelet factor 4 (PF4)/CXCL4. Here, we show that the intra-α-granular proteoglycan, serglycin (SRGN), plays a key role in this process by retaining PF4, and perhaps other factors, during MK maturation. Immature, SRGN–/– MKs released ~80% of their PF4, and conditioned media from these cells negatively affected wild-type MK differentiation in vitro. This was replicated in wild-type MKs by treatment with the polycation surfen, a known inhibitor of glycosaminoglycan (GAG)/protein interactions. In …

Abcg5/Abcg8-Independent Mechanisms Fail To Maintain Sterol Balance In Mice Fed A High-Cholesterol Diet, Garrett B. Anspach, Rupinder Kaur, Isha Chauhan, Erika L. Savage, Brittney Poole, Victoria P. Noffsinger, Xiaoming Fu, Zeneng Wang, Clairity Voy, Ryan E. Temel, Scott M. Gordon, Robert N. Helsley, Gregory A. Graf

Saha Cardiovascular Research Center Faculty Publications

The ABCG5/ABCG8 (G5G8) sterol transporter opposes the accumulation of dietary xenosterols but is also the primary mediator of biliary cholesterol secretion. In humans and in mouse models of disrupted biliary cholesterol secretion, fecal neutral sterols (FNSs) remain constant, indicating the presence of an alternate pathway for cholesterol excretion. Transintestinal cholesterol elimination or excretion (TICE) is thought to compensate for biliary disruptions and G5G8 insufficiency. We sought to measure the compensatory increase in intestinal cholesterol secretion and provide mechanistic insight for how TICE maintains sterol balance in the absence of hepatic G5G8. Differences were not observed in FNSs between control, acute, …

Investigating Plk1 In Pulmonary Fibrosis, Tempany Arbogast

Theses and Dissertations--Toxicology and Cancer Biology

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease, with a median survival of only 2–3 years following diagnosis. In the United States, the disease contributes to more than 40,000 deaths annually, underscoring its severe clinical burden. Alveolar type II (AT2) lung epithelial cells serve as progenitors that maintain alveolar integrity by replenishing epithelial populations and producing surfactants, while fibroblasts and myofibroblasts regulate the extracellular matrix and structural support. In pulmonary fibrosis (PF) injury to AT2 cells promotes cytokine and growth factor release, driving inflammation, fibroblast proliferation, myofibroblast accumulation, and excessive extracellular matrix deposition. Aberrant AT2 cell …

Apoa2 Increases Cholesterol Efflux Capacity To Plasma Hdl By Displacing The C-Terminus Of Resident Apoa1, Snigdha Sarkar, Jamie Morris, Youngki You, Hannah Sexmith, Scott E. Street, Stephanie M. Thibert, Isaac K. Attah, Chelsea M. Hutchinson Bunch, Irina V. Novikova, James E. Evans, Amy S. Shah, Scott M. Gordon, Jere P. Segrest, Karin E. Bornfeldt, Tomas Vaisar, Jay W. Heinecke, W. Sean Davidson, John T. Melchior

Saha Cardiovascular Research Center Faculty Publications

Abstract The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity. APOA2 likewise increased the cholesterol efflux capacity of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up …

Untargeted Lipidomics Reveals Novel Hdl Metabotypes And Lipid-Clinical Correlates, Peer W. F. Karmaus, Scott M. Gordon, Marcus Y. Chen, Alison A. Motsinger-Reif, Rodney W. Snyder, Timothy R. Fennell, Suramya Waidyanatha, Reshan A. Fernando, Alan T. Remaley, Michael B. Fessler

Saha Cardiovascular Research Center Faculty Publications

Plasma high-density lipoprotein (HDL), originally studied for its role in lipid transport, is now appreciated to have wide-ranging biological functions that become defective during disease. While >200 lipids have collectively been detected in HDL, published HDL lipidomic analyses in different diseases have commonly been targeted to prespecified subsets of lipids. Here, we report the results of untargeted lipidomic analysis of HDL isolated from 101 subjects referred for computed tomographic coronary imaging for whom multiple additional clinical and lipoprotein metadata were measured. Unsupervised clustering of the total HDL lipidome revealed that the subjects fell into one of two discrete groups, herein …

Tissue Plasminogen Activator Associated Pulmonary Hemorrhage In Patient With Acta2-Associated Arteriopathy, Travis G. Hughes, Mark A. Wurth, Mary Burchett Sheppard

Saha Cardiovascular Research Center Faculty Publications

Pulmonary hemorrhage after administration of tissue plasminogen activator (tPA) is a rare complication. We present a 15- year-old boy with a heterozygous pathogenic variant in ACTA2 who presented with right brachial artery aneurysm thrombosis treated initially with tPA, resulting in pulmonary hemorrhage. We hypothesize that the underlying pulmonary abnormalities caused by the pathogenic ACTA2 variant may be a risk factor for pulmonary hemorrhage after tPA administration. (J Vasc Surg Cases Innov Tech 2024;10:101558.)

Enhancement Of High-Density Lipoprotein-Associated Protease Inhibitor Activity Prevents Atherosclerosis Progression, Maura Mobilia, Alexander A. Karakashian, Khaga R. Neupane, Olivia Hage, Callie Whitus, Abigail Carter, Clairity Voy, Lance A. Johnson, Gregory A. Graf, Scott M. Gordon

Saha Cardiovascular Research Center Faculty Publications

Background and aims: Inflammatory cells within atherosclerotic lesions secrete proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We previously reported interaction of endogenous protease-inhibitor proteins with high- density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as a modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression.

Methods: We …

Antisense Oligonucleotide Targeting Hepatic Serum Amyloid A Limits The Progression Of Angiotensin Ii-Induced Abdominal Aortic Aneurysm Formation, Preetha Shridas, Ailing Ji, Andrea C. Trumbauer, Victoria P. Noffsinger, Luke W. Meredith, Frederick C. De Beer, Adam E. Mullick, Nancy R. Webb, Dennis G. Karounos, Lisa R. Tannock

Saha Cardiovascular Research Center Faculty Publications

Background and aims: Obesity increases the risk for abdominal aortic aneurysms (AAA) in humans and enhances angiotensin II (AngII)-induced AAA formation in C57BL/6 mice. We reported that deficiency of Serum Amyloid A (SAA) significantly reduces AngII-induced inflammation and AAA in both hyperlipidemic apoE-deficient and obese C57BL/6 mice. The aim of this study is to investigate whether SAA plays a role in the progression of early AAA in obese C57BL/6 mice.

Methods: Male C57BL/6J mice were fed a high-fat diet (60% kcal as fat) throughout the study. After 4 months of diet, the mice were infused with AngII until the end …

Abdominal Aortic Aneurysms And Platelets: Infiltration, Inflammation, And Elastin Disintegration, Bowen Li, Hong S. Lu, Alan Daugherty

Saha Cardiovascular Research Center Faculty Publications

No abstract provided.

Inflammation And Tumor Progression: The Differential Impact Of Saa In Breast Cancer Models, Daniel Wilhelm Olivier, Carla Eksteen, Manisha Du Plessis, Louis De Jager, Lize Engelbrecht, Nathaniel Wade Mcgregor, Preetha Shridas, Frederick C. De Beer, Willem J. S. De Villiers, Etheresia Pretorius, Anna-Mart Engelbrecht

Saha Cardiovascular Research Center Faculty Publications

Background: Previous research has shown that the Serum Amyloid A (SAA) protein family is intricately involved in inflammatory signaling and various disease pathologies. We have previously demonstrated that SAA is associated with increased colitis disease severity and the promotion of tumorigenesis. However, the specific role of SAA proteins in breast cancer pathology remains unclear. Therefore, we investigated the role of systemic SAA1 and SAA2 (SAA1/2) in a triple-negative breast cancer mouse model.

Methods: Syngeneic breast tumors were established in wild-type mice, and mice lacking the SAA1/2 (SAADKO). Subsequently, tumor volume was monitored, species survival determined, the inflammatory profiles of mice …

Novel Endoscopic Approach For Treatment Of Malignant Tracheoesophageal Fistula (Tef): A Case Report, Haris Zia, Matthew D. Mccoy, Jamie L. Sturgill, Walid Hadid, Ashish P. Maskey

Markey Cancer Center Faculty Publications

Cardiac septal occluder (CSO) can be used endoscopically in treatment of tracheoesophageal fis- tula (TEF). We present a case of metastatic cervical cancer with direct tracheal invasion resulting in malignant TEF treated previously with radiotherapy and tracheal stenting twice. This TEF was closed by CSO - patent foramen ovale (PFO) occluder as palliative management to prevent recur- rent aspiration pneumonia, decrease morbidity and improve quality of life.

Deficiency Of Acute-Phase Serum Amyloid A Exacerbates Sepsis-Induced Mortality And Lung Injury In Mice, Ailing Ji, Andrea C. Trumbauer, Victoria P. Noffsinger, Luke W. Meredith, Brittany Dong, Qian Wang, Ling Guo, Xiangan Li, Frederick C. De Beer, Nancy R. Webb, Lisa R. Tannock, Marlene E. Starr, Christopher M. Waters, Preetha Shridas

Saha Cardiovascular Research Center Faculty Publications

Serum amyloid A (SAA) is a family of proteins, the plasma levels of which may increase >1000-fold in acute inflammatory states. We investigated the role of SAA in sepsis using mice deficient in all three acute-phase SAA isoforms (SAA-TKO). SAA deficiency significantly increased mortality rates in the three experimental sepsis mouse models: cecal ligation and puncture (CLP), cecal slurry (CS) injection, and lipopolysaccharide (LPS) treatments. SAA-TKO mice had exacerbated lung pathology compared to wild-type (WT) mice after CLP. A bulk RNA sequencing performed on lung tissues excised 24 h after CLP indicated significant enrichment in the expression of genes associated …

Ecohiv-Infected Mice Show No Signs Of Platelet Activation, Hammodah Rawhi Hammodah Alfar, Dominic Ngima Nthenge-Ngumbau, Kathryn E. Saatman, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Platelets express several surface receptors that could interact with different viruses. To understand the mechanisms of HIV-1′s interaction with platelets, we chose the EcoHIV model. While EcoHIV is an established model for neuroAIDS, its effects on platelets are ill-defined. Our results indicate that EcoHIV behaves differently from HIV-1 and is cleared from circulation after 48 h post- infection. The EcoHIV course of infection resembles an HIV-1 infection under the effects of combined antiretroviral therapy (cART) since infected mice stayed immunocompetent and the virus was readily detected in the spleen. EcoHIV-infected mice failed to become thrombocytopenic and showed no signs of …

Loss Of Carnitine Palmitoyltransferase 1a Reduces Docosahexaenoic Acid-Containing Phospholipids And Drives Sexually Dimorphic Liver Disease In Mice, Mikala M. Zelows, Corissa Cady, Nikitha Dharanipragada, Anna E. Mead, Zachary A. Kipp, Evelyn A. Bates, Venkateshwari Varadharajan, Rakhee Banerjee, Se-Hyung Park, Nathan R. Shelman, Harrison A. Clarke, Tara R. Hawkinson, Terrymar Medina, Ramon C. Sun, Todd A. Lydic, Terry D. Hinds, Jr., J. Mark Brown, Samir Softic, Gregory A. Graf, Robert N. Helsley

Saha Cardiovascular Research Center Faculty Publications

Background and aims: Genome and epigenome wide association studies identified variants in carnitine palmitoyltransferase 1a (CPT1a) that associate with lipid traits. The goal of this study was to determine the role of liver-specific CPT1a on hepatic lipid metabolism.

Approach and results: Male and female liver-specific knockout (LKO) and littermate controls were placed on a low-fat or high-fat diet (60% kcal fat) for 15 weeks. Mice were necropsied after a 16 h fast, and tissues were collected for lipidomics, matrix-assisted laser desorption ionization mass spectrometry imaging, kinome analysis, RNA-sequencing, and protein expression by immunoblotting. Female LKO mice had increased serum alanine …

Α-Synuclein Is The Major Platelet Isoform But Is Dispensable For Activation, Secretion, And Thrombosis, Alexis N. Smith, Smita Joshi, Harry Chanzu, Hammodah Rawhi Hammodah Alfar, Kanakanagavalli Shravani Prakhya, Sidney W. Whiteheart

Saha Cardiovascular Research Center Faculty Publications

Platelets play many roles in the vasculature ensuring proper hemostasis and maintaining integrity. These roles are facilitated, in part, by cargo molecules released from platelet granules via Soluble NSF Attachment Protein Receptor (SNARE) mediated membrane fusion, which is controlled by several protein-protein interactions. Chaperones have been characterized for t-SNAREs (i.e. Munc18b for Syntaxin-11), but none have been clearly identified for v-SNAREs. α- Synuclein has been proposed as a v-SNARE chaperone which may affect SNARE-complex assembly, fusion pore opening, and thus secretion. Despite its abundance and that it is the only isoform present, α-synuclein’s role in platelet secretion is uncharacterized. In …

Inflammasome Activation And Pyroptosis Mediate Coagulopathy And Inflammation In Salmonella Systemic Infection, Ankit Pandeya, Yan Zhang, Jian Cui, Ling Yang, Jeffery Li, Guoying Zhang, Congqing Wu, Zhenyu Li, Yinan Wei

Saha Cardiovascular Research Center Faculty Publications

Inflammasome activation is a critical defense mechanism against bacterial infection. Previous studies suggest that inflammasome activation protects against Salmonella oral infection. Here we find inflammasome activation plays a critical role in the pathogenesis of Salmonella systemic infection. We show that in a systemic infection model by i.p. injection of Salmonella, deficiency of caspase-1 or gasdermin-D prolonged survival time, reduced plasma concentrations of the proinflammatory cytokines IL-1β, IL-6 and TNFα. These deficiencies also protected against coagulopathy during Salmonella infection as evidenced by diminished prolongation of prothrombin time and increase in plasma thrombin-antithrombin complex concentrations in the caspase-1 or gasdermin-D deficient mice. …

Activated Protein C, Protein S, And Tissue Factor Pathway Inhibitor Cooperate To Inhibit Thrombin Activation, Xian Li, Xiaohong Song, Dlovan F. D. Mahmood, Martha M. S. Sim, Sara J. Bidarian, Jeremy P. Wood

Saha Cardiovascular Research Center Faculty Publications

Introduction: Thrombin, the enzyme which converts fibrinogen into a fibrin clot, is produced by the prothrombinase complex, composed of factor Xa (FXa) and factor Va (FVa). Down-regulation of this process is critical, as excess thrombin can lead to life-threatening thrombotic events. FXa and FVa are inhibited by the anticoagulants tissue factor pathway inhibitor alpha (TFPIα) and activated protein C (APC), respectively, and their common cofactor protein S (PS). However, prothrombinase is resistant to either of these inhibitory systems in isolation. Materials and methods: We hypothesized that these anticoagulants function best together, and tested this hypothesis using purified proteins and plasma-based …

Novel Strategies In Antithrombotic Therapy: Targeting Thrombosis While Preserving Hemostasis, Martha M. S. Sim, Semekidus Shiferawe, Jeremy P. Wood

Saha Cardiovascular Research Center Faculty Publications

Antithrombotic therapy is a delicate balance between the benefits of preventing a thrombotic event and the risks of inducing a major bleed. Traditional approaches have included antiplatelet and anticoagulant medications, require careful dosing and monitoring, and all carry some risk of bleeding. In recent years, several new targets have been identified, both in the platelet and coagulation systems, which may mitigate this bleeding risk. In this review, we briefly describe the current state of antithrombotic therapy, and then present a detailed discussion of the new generation of drugs that are being developed to target more safely existing or newly identified …

Protocol For Optimizing Production And Quality Control Of Infective Ecohiv Virions, Hammodah Rawhi Hammodah Alfar, Daphne N. Pariser, Harry Chanzu, Smita Joshi, Daniёlle M. Coenen, Joshua Lykins, Kanakanagavalli Shravani Prakhya, Mary Jane Potash, Wei Chao, Jennifer Kelschenbach, David J. Volsky, Kelly Metcalf-Pate

Saha Cardiovascular Research Center Faculty Publications

EcoHIV is a model of HIV infection that recapitulates aspects of HIV-1 pathology in mice. However, there are limited published protocols to guide EcoHIV virion production. Here, we present a protocol for producing infective EcoHIV virions and essential quality controls. We describe steps for viral purification, titering, and multiple techniques to analyze infection efficacy. This protocol produces high infectivity in C57BL/6 mice which will aid investigators in generating preclinical data.

Cell-Free, High-Density Lipoprotein-Specific Phospholipid Efflux Assay Predicts Incident Cardiovascular Disease, Masaki Sato, Edward B. Neufeld, Martin P. Playford, Yu Lei, Alexander V. Sorokin, Angel M. Aponte, Lita A. Freeman, Scott M. Gordon, Amit K. Dey, Kianoush Jeiran, Masato Hamasaki, Maureen L. Sampson, Robert D. Shamburek, Jingrong Tang, Marcus Y. Chen, Kazuhiko Kotani, Josephine L. C. Anderson, Robin P. F. Dullaart, Nehal N. Mehta, Uwe T. F. Tietge, Alan Thomas Remaley

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND. Cellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL- cholesterol (HDL-C) but is not suitable as a routine clinical METHODS. We developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein–mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD …

Functional Exploration Of Conserved Sequences In The Distal Face Of Angiotensinogen - Brief Report, Naofumi Amioka, Chia-Hua Wu, Hisashi Sawada, Sohei Ito, Alex C. Pettey, Congqing Wu, Jessica J. Moorleghen, Deborah A. Howatt, Gregory A. Graf, Craig W. Vander Kooi, Alan Daugherty, Hong S. Lu

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: Angiotensinogen (AGT) is an essential component in the renin-angiotensin system. AGT has highly conserved sequences in the loop and β-sheet regions among species; however, their functions have not been studied.

METHODS: Adeno-associated viral vector (AAV) serotype 2/8 encoding mouse AGT with mutations of conserved sequences in the loop (AAV.loop-Mut), β-sheet (AAV.βsheet-Mut), or both regions (AAV.loop/βsheet-Mut) was injected into male hepatocyte-specific AGT-deficient (hepAGT−/− ) mice in an LDL (low-density lipoprotein) receptor–deficient background. AAV containing mouse wild-type AGT (AAV.mAGT) or a null vector (AAV.null) were used as controls. Two weeks after AAV administration, all mice were fed a western diet for …

Fructose Induced Khk-C Can Increase Er Stress Independent Of Its Effect On Lipogenesis To Drive Liver Disease In Diet-Induced And Genetic Models Of Nafld, Se-Hyung Park, Robert N. Helsley, Taghreed Fadhul, Jennifer L. S. Willoughby, Leila Noetzli, Ho-Chou Tu, Marie H. Solheim, Shiho Fujisaka, Hui Pan, Jonathan M. Dreyfuss, Joanna Bons, Jacob Rose, Christina D. King, Birgit Schilling, Aldons J. Lusis, Calvin Pan, Manoj Gupta, Rohit N. Kulkarni, Kevin Fitzgerald, Philip A. Kern, Senad Divanovic, C. Ronald Kahn, Samir Softic

Saha Cardiovascular Research Center Faculty Publications

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and …

Assessing Hip Joint–Related Structure And Patient-Reported Outcomes In People With Marfan Syndrome, Ziyu Zhang, Wen Dai, Wen Zhu, Maya Rodriguez, Hayley Lund, Yuhe Xia, Yiliang Chen, Mary Rau, Ellen Anje Schneider, Mary Beth Graham, Shawn Jobe, Demin Wang, Weiguo Cui, Renren Wen, Sidney W. Whiteheart, Jeremy P. Wood, Roy Silverstein, Jeffery S. Berger, Lisa Baumann Kreuziger, Tessa J. Barrett, Ze Zheng

Saha Cardiovascular Research Center Faculty Publications

Background: Patients with COVID-19 have a higher risk of thrombosis and thromboembolism, but the underlying mechanism(s) remain to be fully elucidated. In patients with COVID-19, high lipoprotein(a) (Lp(a)) is positively associated with the risk of ischemic heart disease. Lp(a), composed of an apoB-containing particle and apolipoprotein(a) (apo(a)), inhibits the key fibrinolytic enzyme, tissue-type plasminogen activator (tPA). However, whether the higher Lp(a) associates with lower tPA activity, the longitudinal changes of these parameters in hospitalized patients with COVID-19, and their correlation with clinical outcomes are unknown.

Objectives: To assess if Lp(a) associates with lower tPA activity in COVID-19 patients, and how …

Ketohexokinase-C Regulates Global Protein Acetylation To Decrease Carnitine Palmitoyltransferase 1a-Mediated Fatty Acid Oxidation, Robert N. Helsley, Se-Hyung Park, Hemendra J. Vekaria, Patrick G. Sullivan, Lindsey R. Conroy, Ramon Sun, María Del Mar Romero, Laura Herrero, Joanna Bons, Christina D. King, Jacob Rose, Jesse G. Meyer, Birgit Schilling, C. Ronald Kahn, Samir Softic

Saha Cardiovascular Research Center Faculty Publications

Background & Aims: The consumption of sugar and a high-fat diet (HFD) promotes the development of obesity and metabolic dysfunction. Despite their well-known synergy, the mechanisms by which sugar worsens the outcomes associated with a HFD are largely elusive. Methods: Six-week-old, male, C57Bl/6 J mice were fed either chow or a HFD and were provided with regular, fructose- or glucose-sweetened water. Moreover, cultured AML12 hepatocytes were engineered to overexpress ketohexokinase-C (KHK–C) using a lentivirus vector, while CRISPR-Cas9 was used to knockdown CPT1a. The cell culture experiments were complemented with in vivo studies using mice with hepatic overexpression of KHK–C and …

Development Of A Definition Of Postacute Sequelae Of Sars-Cov-2 Infection, Tanayott Thaweethai, Sarah E. Jolley, Elizabeth W. Karlson, Emily B. Levitan, Bruce Levy, Grace A. Mccomsey, Lisa Mccorkell, Girish N. Nadkarni, Sairam Parthasarathy, Upinder Singh, Tiffany A. Walker, Caitlin A. Selvaggi, Daniel J. Shinnick, Carolin C. M. Schulte, Rachel Atchley-Challenner, Recover Consortium Authors, Leora I. Horwitz, Andrea S. Foulkes

Saha Cardiovascular Research Center Faculty Publications

IMPORTANCE SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.

OBJECTIVE To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.

DESIGN, SETTING, AND PARTICIPANTS Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, …

Serum Amyloid A Augments The Atherogenic Effects Of Cholesteryl Ester Transfer Protein, Ailing Ji, Andrea C. Trumbauer, Victoria P. Noffsinger, Frederick C. De Beer, Nancy R. Webb, Lisa R. Tannock, Preetha Shridas

Saha Cardiovascular Research Center Faculty Publications

Serum amyloid A (SAA) is predictive of CVD in humans and causes atherosclerosis in mice. SAA has many proatherogenic effects in vitro. However, HDL, the major carrier of SAA in the circulation, masks these effects. The remodeling of HDL by cholesteryl ester transfer protein (CETP) liberates SAA restoring its proinflammatory activity. Here, we investigated whether deficiency of SAA suppresses the previously described proatherogenic effect of CETP. ApoE¡/¡ mice and apoE¡/¡ mice deficient in the three acute-phase isoforms of SAA (SAA1.1, SAA2.1, and SAA3; “apoE¡/¡ SAA-TKO”) with and without adeno-associated virus-mediated expression of CETP were studied. There was no effect of …

Spatial Metabolomics Reveals Glycogen As An Actionable Target For Pulmonary Fibrosis, Lindsey R. Conroy, Harrison A. Clarke, Derek B. Allison, Samuel Santos Valenca, Qi Sun, Tara R. Hawkinson, Lyndsay E. A. Young, Juanita E. Ferreira, Autumn V. Hammonds, Jaclyn B. Dunne, Robert J. Mcdonald, Kimberly J. Absher, Brittany Dong, Ronald C. Bruntz, Kia H. Markussen, Jelena A. Juras, Warren J. Alilain, Jinze Liu, Matthew S. Gentry, Peggi M. Angel, Christopher M. Waters, Ramon C. Sun

Saha Cardiovascular Research Center Faculty Publications

Matrix assisted laser desorption/ionization imaging has greatly improved our understanding of spatial biology, however a robust bioinformatic pipeline for data analysis is lacking. Here, we demonstrate the application of high- dimensionality reduction/spatial clustering and histopathological annotation of matrix assisted laser desorption/ionization imaging datasets to assess tissue metabolic heterogeneity in human lung diseases. Using metabolic features identified from this pipeline, we hypothesize that metabolic channeling between glycogen and N-linked glycans is a critical metabolic process favoring pulmonary fibrosis progression. To test our hypothesis, we induced pulmonary fibrosis in two different mouse models with lysosomal glycogen utilization deficiency. Both mouse models displayed …