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.

Vascular Mechanisms Of Rhabdomyolysis-Induced Acute Kidney Injury, Jeremiah Moyinolu Afolabi

Theses and Dissertations (ETD)

In patients with rhabdomyolysis, the overwhelming release of myoglobin into circulation is the primary cause of kidney injury. Myoglobin causes direct kidney injury as well as severe renal vasoconstriction. An increase in renal vascular resistance (RVR) results in renal blood flow (RBF) and glomerular filtration rate (GFR) reduction, tubular injury, and acute kidney injury (AKI). The mechanisms that underlie rhabdomyolysis-induced AKI are not fully understood but may involve the local production of vasoactive mediators in the kidney. Myoglobin stimulated endothelin-1 (ET-1) production in proximal tubular cells, an effect driven by NADPH oxidase-dependent oxyradical generation. Rats subjected to glycerol-induced rhabdomyolysis also …

Outcomes Among Heart Failure Patients Hospitalized For Acute Pulmonary Embolism And Covid-19 Infection: Insight From The National Inpatient Sample, Bruce Adrian Casipit, Sahana Tito, Isaac Ogunmola, Abiodun Idowu, Shivaraj Patil, Kevin Lo, Behnam Bozorgnia

Einstein Health Papers

There is paucity of data regarding the outcomes of hospitalized acute pulmonary embolism (PE) patients with heart failure (HF) and Coronavirus Disease 2019 (COVID-19) infection. We utilized the 2020 National Inpatient Sample (NIS) Database in conducting a retrospective cohort study to investigate the outcomes of hospitalized acute PE patients with HF and COVID-19, looking at its impact on in-hospital mortality, thrombolysis, and thrombectomy utilization as well as hospital length of stay (LOS). A total of 23,413 hospitalized acute PE patients with HF were identified in our study, of which 1.26% (n = 295/23,413) had COVID-19 infection. Utilizing a stepwise survey …

Impact Of Passive Leg Movement On Lower Limb Vascular Function In Patients With A Spinal Cord Injury, Christian D. Sanchez Tato, Elizabeth J. Pekas, Michael F. Allen, Cody P. Anderson, Song-Young Park

UNO Student Research and Creative Activity Fair

Background: Individuals with spinal cord injuries (SCI) are at a greater risk for developing cardiovascular diseases. Of note, post injury mediated increases in physical inactivity leads to muscle atrophy, which also results in vascular dysfunction in this population. Although a growing body of evidence suggests that passive leg movement (PLM) may be a useful exercise modality to improve peripheral blood flow and skeletal muscle activation in individuals with limited mobility, few studies have examined the impact of PLM on local skeletal muscle blood flow. Therefore, there is a need to examine the impact of PLM on lower limb vascular function …

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 …

Change In Basic Pulmonary Function With Change In Altitude, Jaden Arnold, Mindy Cook, Bivash Neupane, Erika Noonan Md, Rex Ripplinger Md

Annual Research Symposium

No abstract provided.

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 …

Closed-Loop Modeling Of Central And Intrinsic Cardiac Nervous System Circuits Underlying Cardiovascular Control, Michelle M. Gee, Abraham M. Lenhoff, James S. Schwaber, Babatunde A. Ogunnaike, Rajanikanth Vadigepalli

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The baroreflex is a multi-input, multi-output physiological control system that regulates blood pressure by modulating nerve activity between the brainstem and the heart. Existing computational models of the baroreflex do not explicitly incorporate the intrinsic cardiac nervous system (ICN), which mediates central control of heart function. We developed a computational model of closed-loop cardiovascular control by integrating a network representation of the ICN within central control reflex circuits. We examined central and local contributions to the control of heart rate, ventricular functions, and respiratory sinus arrhythmia (RSA). Our simulations match the experimentally observed relationship between RSA and lung tidal volume. …

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. …

Medical Professionals’ Perspective On Safety And Efficacy Of Early Mobilization In Acute Heart Failure Patients, Kevin Triangto, Febrian M. Santausa, Basuni Radi, Bambang Budi Siswanto

Journal of the Hong Kong College of Cardiology

Acute heart failure (HF) patients most of the time presents with hemodynamic instability, which often leads to prolonged bedrest. Newer studies had shown that early mobilization for HF patients would lead to better outcomes. However, the early mobilization practice has not always been done due to several barriers in the medical professionals’ perspective, especially regarding safety and efficacy. Prior studies had shown that medical professionals’ views would greatly affect patients’ perspectives, especially in HF rehabilitation. This study is aimed to describe medical professionals’ views on the safety of early mobilization for HF. It was then revealed that General Practitioners’ (GP) …

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 …