bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smooth Muscle Specific Glyceraldehyde‐3′‐phosphate dehydrogenase (GAPDH) Reduces DNA Damage, Decreases Cell Apoptosis, Suppresses Atherosclerosis and Promotes the Stable Plaque Phenotype
Authors: Sukhanov Sergiy , Hou Xuwei , Snarski Patricia , Yoshida Tadashi , Delafontaine Patrice 
Published: June 2021

GAPDH is a glycolytic enzyme with a multiple glycolysis‐unrelated functions. We have shown that GAPDH protected smooth muscle cells (SMC) against oxidant‐induced apoptosis via upregulation of Ape1 endonuclease, the major DNA repair enzyme. We also found that GAPDH levels were reduced in atherosclerotic plaque SMC. We hypothesized that SMC‐specific GAPDH overexpression will reduce atherosclerosis. We generated Apoe‐null mice with SM22α promoter‐driven GAPDH overexpression (SM‐GAPDH mice). GAPDH protein levels were increased >2‐fold (P<0.05) in aortas isolated from SM‐GAPDH vs. Apoe‐null controls. SM‐GAPDH mice have BW and BP similar to control. Aortic circumference, lumen area and media area were not changed by GAPDH overexpression. SMC GAPDH did not change pulse wave velocity (SM‐GAPDH, 1.1±0.1 m/s, control, 1.2±0.3 m/s) (ultrasound imaging) as well as endothelium‐dependent and ‐independent vascular responses to PE, Ach or SNP (organ chamber assay with thoracic aortic rings). High‐cholesterol fed SM‐GAPDH had reduced atherosclerotic burden (H&E‐stained aortic valve cross‐sections: 28±3% decrease, P<0.05), elevated plaque SMC levels (IHC for a‐SM actin, 3.1‐fold increase, P<0.01; IHC for calponin, 3.8‐fold increase, P<0.05), increased plaque collagen (Trichrome, 2.1‐fold increase, P<0.05), reduced plaque SMC apoptosis (TUNEL assay with IHC for calponin, 3.2‐fold decrease, IHC for cleaved caspase‐3, 2.6‐fold decrease both are P<0.05) without changes in macrophages (IHC with Mac3, P=NS). Aortas isolated from SM‐GAPDH have increased Ape1 endonuclease (31±5% increase, P<0.05), reduced cleaved PARP (apoptotic marker, 74±12% decrease, P<0.001) and decreased oxidative DNA damage (AP sites assay, 2.5‐fold decrease, P<0.05; pSer139 histone H2AX, 33±3% decrease, P<0.05) compared to controls. Plaques in SM‐GAPDH had thicker SMC‐rich fibrous plaque cap (3.5‐fold increase, P<0.05) and decreased area of necrotic core (1.8‐fold reduction, P<0.05) suggesting enhanced plaque stability. These data taken together with our in vitro findings indicate that Ape1 upregulation mediates GAPDH effect on DNA and apoptosis. Stimulation of GAPDH/Ape1 axis is a novel potential anti‐atherosclerotic therapy.Support or Funding InformationNIH/NHLBI R01HL070241 (P.D.), American Heart Association Grant‐in‐Aid 13GRNT17230069 (S.S.), and University of Missouri School of Medicine Bridge Fund (S.S.)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Aqueous Seed Extract of Carica Papaya on Lipid Profile and Anti‐Atherogenic Index of Wistar Rat Following Cholesterol Administration
Authors: Inneh Churchill , Uhonmoibhi samuel , Oghenakhogie Momodu 
Published: June 2021

BackgroundHypercholesterolemia is a major component in the formation of atherogenic plaques which is the predominant risk factor implicated in the development of cardiovascular diseases (Rerkasem et al., 2008). The focus of our research lab is to investigate natural‐herbal preparations with anti‐atherogenic potential. Available scientific investigation(s) had reported the use different parts of Carica Papaya plant in the treatment of different ailments including cardiovascular diseases (Sudhakar and Vidhya, 2014). The aim of this study was to investigate the effect of aqueous seed extract of Carica Papaya on lipid profile and anti‐atherogenic index of Wistar rats exposed to high cholesterol.MethodCarica papaya fruit were harvested from the University of Benin farm project. The seeds were extracted from the fruit and dried for eight (8) weeks at room temperature. The seeds were milled to powdered form and extracted using Soxlet extractor. Thirty five (35) Adult Wistar rats weighing between 150–200g were used for this study. The animals were kept in the animal holdings of the Department of Anatomy, University of Benin and were allowed to acclimatize for two weeks. All experiments were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. The animals were assigned into seven groups with five (5) animals in each group. Animals in group A served as control; group B1 animals were administered with 100 mg/kg body weight of cholesterol dust for two weeks; group B2 animals were administered with 100 mg/kg body weight of cholesterol dust for four weeks; group C1 animals were administered with 400mg/kg body weight of aqueous seed extract of Carica papaya for two weeks; group C2 were administered with 400mg/kg body weight of aqueous seed extract of Carica papaya for four weeks; group D1 and D2 animals were co‐administered with 100 mg/kg body weight of cholesterol dust and 400mg/kg body weight of aqueous seed extract of Carica papaya for two weeks and four weeks respectively. Cholesterol dust was purchased from Sigma Aldrich Chemical Co. (St. Louis, MO, USA).ResultsAdministration of Carica Papaya seed extract to rats exposed to high cholesterol significantly (P<0.001) reduced serum concentration of total cholesterol (TC), triglycerides, very low density lipoproteins (VLDL), low density lipoproteins (LDL) while there was a significant increase (P< 0.01) in high density lipoproteins (HDL). Anti‐atherogenic index (AAI) of both normal and cholesterol administered rats treated with the extract was significantly (P<0.001) higher compared with the untreated cholesterol administered rats.ConclusionThe present study has shown that Carica Papaya seed extract possesses anti‐hyperlipidemic as well as anti‐atherogenic activities.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
KCa3.1 contributes to atherosclerotic lesion development induced by low, oscillatory flow
Authors: Bowles Doug K , Tharp Darla L 
Published: June 2021

Increased expression of KCa3.1 has been found in vascular smooth muscle (VSM), macrophages and T cells in atherosclerotic lesions from humans and mice. Proliferating VSM cells increase expression of KCa3.1, such that it becomes a dominant K+ channel and contributes to VSM cell migration. Previously, we showed that the KCa3.1 inhibitor, TRAM‐34, could inhibit coronary neointimal development following coronary balloon injury in swine. In the current study, we tested the role of KCa3.1 in atherosclerotic lesion development using two mouse models of atherosclerosis. First, partial carotid ligation (PCL), which produces a low, oscillatory (i.e. atheroprone) flow pattern in the left carotid artery was performed on 6–8 week old male Apoe−/− mice. Mice were subsequently placed on a Western diet (WD; TD.88137, Teklad) for 4 weeks and received daily s.c. injections of TRAM‐34 (120 mg/kg) or equal volumes of vehicle (peanut oil). To directly test the role of KCa3.1 we used CRISPR/Cas9 to generate KCa3.1−/−Apoe−/− (DKO) mice. Subsequently, we examined lesion development in the brachiocephalic artery (BCA) of DKO vs. Apoe−/− male mice on a WD for 3 months. In PCL mice, TRAM‐34 treatment reduced lesion size ~50% (p<0.05). In addition, lesions from TRAM‐34 treated mice contained significantly less collagen (6 ± 1% v. 15 ± 2%; p<0.05), fibronectin (14±3% v. 32±3%; p<0.05) and smooth muscle content (19±2% v. 29±3%; p<0.05). Similarly, in BCAs of DKO mice, both lesion size (0.036 vs. 0.118 mm2, p<0.05) and relative stenosis (13.9% vs. 43.0%, p<0.05) were reduced 70% compared to Apoe−/− mice with no effect on medial or lumen area. Neither TRAM‐34 nor KCa3.1 silencing had any effect on total cholesterol or body weight. These data provide the first genetic validation defining a major role of KCa3.1 in lesion development and determining smooth muscle and matrix content of atherosclerotic lesions.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Influence of Fitness on Vascular Function in Young Adults during Acute Inflammation
Authors: Schroeder Elizabeth C , Hilgenkamp Thessa I.M. , Lefferts Wesley K , Baynard Tracy , Fernhall Bo 
Published: June 2021

Acute inflammation is associated with increased risk of cardiovascular events and impairs vascular function. Vascular function in this setting is most often interrogated by assessing endothelial function in conduit arteries, however, less is known regarding the downstream vascular tree including resistance artery and microvasculature function. Vascular dysfunction during acute inflammation may be attenuated by high cardiorespiratory fitness due to its association with improved vascular function and cardiovascular health.PURPOSEDetermine the effect of acute inflammation and fitness on conduit artery, resistance artery, and microvascular function.METHODSVascular function was assessed in 11 low fit (6 male, 24 ± 5 yrs, 22.8 ± 4.3 kg/m2, 34.5 ± 2.9 ml/kg/min) and 12 high fit (5 male, 27 ± 4 yrs, 22.6 ± 1.9 kg/m2, 56.4 ± 9.7 ml/kg/min) participants at baseline and 24h after a typhoid vaccination. Fitness was determined using a maximal treadmill test and those with a VO2peak >75th age‐ and sex‐specific percentile according to the American College of Sports Medicine were considered high fit. Vascular assessments included flow‐mediated dilation (FMD) of the brachial artery via ultrasonography, forearm reactive hyperemia (RH) via venous occlusion plethysmography, and near‐infrared spectroscopy (NIRS) during a 5‐min arterial occlusion. Blood pressure was measured using an oscillometric cuff and C‐reactive protein (CRP) and interleukin‐6 (IL‐6) were assessed via standard ELISA techniques.RESULTSAcute inflammation was induced, as evident by increases in IL‐6 and CRP (p<0.01, see Table). Mean arterial pressure did not change in either group (low fit: 92 ± 9 to 91 ± 8; high fit: 92 ± 10 to 91 ± 7). FMD was lower in the high fit group, yet both groups reduced FMD at 24h, even after controlling for shear rate (p<0.05). No effect of acute inflammation was observed for forearm RH or NIRS (p>0.05). High fit individuals, however, had greater microvascular reactivity with a quicker ability to accommodate increased blood flow (time to peak, group effect, p<0.05).CONCLUSIONFitness did not alter the vascular response to acute inflammation, regardless of the level along the vascular tree. Both groups showed reductions in conduit artery endothelial function and no change in resistance artery or microcirculatory function, suggesting acute inflammation has non‐uniform effects on vascular function. Cardiorespiratory fitness did not influence the arterial response to inflammation, at least in this young, healthy population. Future studies need to evaluate the effects of acute inflammation in older individuals including those who are healthy and those with chronic health conditions.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
High‐endothelial cell‐derived S1P regulates dendritic cell localization and vascular integrity in the lymph node
Authors: Simmons Szandor , Sasaki Naoko , Umemoto Eiji , Uchida Yutaka , Fukuhara Shigetomo , Kitazawa Yusuke , Okudaira Michiyo , Inoue Asuka , Tohya Kazuo , Aoi Keita , Aoki Junken , Mochizuki Naoki , Matsuno Kenjiro , Takeda Kiyoshi , Kuebler Wolfgang M. , Miyasaka Masayuki , Ishii Masaru 
Published: June 2021

While the sphingosine‐1‐phosphate (S1P)/sphingosine‐1‐phosphate receptor‐1 (S1PR1) axis is critically important for lymphocyte egress from lymphoid organs, S1PR1 activation also occurs in vascular endothelial cells (ECs), including those of the high‐endothelial venules (HEVs) that mediate lymphocyte immigration into lymph nodes (LNs). To understand the functional significance of the S1P/S1PR1‐Gi axis in HEVs, we generated Lyve1‐Spns2Δ/Δ conditional knockout mice for the S1P‐transporter Spinster‐homologue‐2 (Spns2), as HEVs express Lyve1 during development. In these mice, HEVs appeared apoptotic and were severely impaired in function, morphology and size; leading to markedly hypotrophic peripheral LNs. Within these LN, dendritic cells (DCs) were unable to interact with HEVs, which was also observed in VEcad‐CREERT2‐S1PR1Δ/Δ mice and wildtype mice treated with S1PR1‐antagonists. Wildtype HEVs treated with S1PR1‐antagonists in vitro, as well as Spns2‐deficient HEVs in vivo, show severely reduced release of the DC‐chemoattractant CCL21. Together, our results reveal that EC‐derived S1P warrants HEV‐integrity through autocrine control of S1PR1‐Gi signaling, and facilitates concomitant HEV‐DC interactions.Support or Funding InformationThis work was supported by Grants‐in‐Aid for Scientific Research (A) from the Japan Society for the Promotion of Science (JSPS; JP25253070 and JP16H02619 to M.I.); Grants‐in‐Aid for Young Scientists (B) from the JSPS (JP26860329 to S.S.); grants from the Takeda Science Foundation (to M.I.); from the Uehara Memorial Foundation (to M.I.); from the Kanae Foundation for the Promotion of Medical Sciences (to M.I.); and from the Kishimoto Foundation (to S.S.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Platelets determine the onset of innate and adaptive immune cell responses Schaubaecher J, Mittmann L, Uhl B, Reichel CA
Authors: Schaubächer Johanna 
Published: June 2021

Neutrophils represent the first immune cells recruited to the site of injury or infection, followed by monocytes and, later on, lymphocytes. In addition to their fundamental role in hemostasis, platelets are increasingly recognized to serve as critical modulators of immune responses. Whereas interactions of platelets with myeloid leukocytes have been extensively studied, the functional relevance of these cellular blood components for the regulation of lymphocyte trafficking remains poorly understood. Employing multi‐channel in vivo microscopy on the mouse cremaster muscle, platelets were found to instantly accumulate in the venular microvasculature upon induction of inflammation right before neutrophils, monocytes, and lymphocytes, but are progressively released from the endothelium into the bloodstream after extravasation of myeloid leukocytes. In this context, platelets divergently control the trafficking of myeloid leukocytes and lymphocytes to inflamed tissue as assessed by multi‐channel flow cytometry analyses in a mouse peritonitis assay: Whereas depletion of platelets severely compromised the extravasation of neutrophils and classical monocytes, the recruitment of CD4+ lymphocytes, CD8+ lymphocytes, and B lymphocytes to the perivascular space was dramatically enhanced. Importantly, depletion of neutrophils in these experiments completely abolished responses of classical monocytes, but did not affect lymphocyte trafficking. In this context, activated platelets were found to upregulate surface expression of adhesion/signaling molecules facilitating interactions with neutrophils such as CD40 and CD40L as well as of factors interfering with lymphocyte activation including programmed death‐ligand 1 (PD‐L1), CD80, and CD86. Blockade of these latter immune checkpoint molecules significantly enhanced lymphocyte responses to the level of platelet‐depleted animals. Thus, our experimental data identify a previously unappreciated functional role of platelets as ‚decision makers' in the immune system that critically regulate the onset of innate and adaptive immune cell responses in inflammatory reactions.Support or Funding InformationThis study was supported by Deutsche Forschungsgemeinschaft (DFG), Sonderforschungs‐bereich (SFB) 914.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Zika Virus Localizes to Vascular Endothelial and Smooth Muscle Cells following In Vivo Infection
Authors: Peruri Alekhya , Brown Isola A.M. , Wang Tony T. , Isakson Brant E. 
Published: June 2021

Zika virus (ZIKV) is a public health concern due to its classification as a bloodborne pathogen. However, the pathology of ZIKV— i.e. its mechanisms of infection – is not been fully understood. We and other researchers have recently discovered that multiple ZIKV strains readily infect primary human endothelial cells (ECs). However, the cellular targets of the virus during in vivo whole animal infection are not known. We investigated the role of the intact vasculature in ZIKV infection and hypothesized that ZIKV will be localized to ECs following in vivo infection.7‐week old male C57Bl/6 mice were treated using an established in vivo animal model of ZIKV infection. Mice received ZIKV strains isolated from either an African (DAK) or South American (PRV) viral outbreak. Mice were sacrificed 7 days post‐infection and we used immunohistochemistry to detect ZIKV expression in collected vessels including the aorta, mesenteric arteries and veins, the renal artery, and the cremasteric and retinal vasculatures. ZIKV virus was labeled anti‐4G2, which marks a viral coat protein of ZIKV, and ECs were labeled with anti‐CD31.Mice treated with the DAK strain showed positive localization in the smooth muscle cells (SMCs) of the cremaster preparation, ECs of mesenteric vessels, and SMCs and ECs of the renal artery. Those treated with the PRV strain also showed localization in the ECs of the cremaster and mesenteric vasculatures, and both the SMCs and ECs of the renal artery. There was no positive ZIKV localization found in the retina.Positive localization of ZIKV in the vascular beds of the cremaster, mesenteric vessels, and renal artery suggests a role for the ECs and SMCs of the vasculature in the pathology of ZIKV infection. Future work will investigate key cellular targets that may be in involved in regulating in vivo ZIKV infection, such as the AXL tyrosine kinase receptor AXL which is required for ZIKV infection in vitro. These and future studies will improve our understanding of the pathology of ZIKV infection.Support or Funding InformationFord Foundation Postdoctoral Grant (IAMB), HL 088554 R01 (BEI)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Traumatic Brain Injury Alters BK Channel Subunit Expression, Localization, and Function in Cerebral Arterial Myocytes
Authors: Evanson Kirk W. , Goldsmith Jacob A. , Ghosh Payal , Levenson Cathy W. 
Published: June 2021

Traumatic brain injury (TBI) induces acute changes in cerebrovascular function, which include alterations to cerebral artery myogenic tone and autoregulation. In arterial smooth muscle cells (myocytes), large‐conductance calcium‐activated potassium (BK) channels play a vital role in modulating plasma membrane potential and myogenic tone. Here, we examined BK channel expression and function in cerebral resistance size arteries one week following moderately‐severe TBI induced by controlled cortical impact with craniotomy. Total BKα (pore‐forming) and β1 (regulatory) subunit expression were reduced one week post‐TBI. Biotinylation of plasma membrane‐bound proteins revealed a compensatory increase of β1 subunits to the plasma membrane following TBI, which normalized single BK channel activation as assessed using patch‐clamp electrophysiology. However, the loss of total BKα subunits resulted in diminished whole cell, transient BK currents. Pressurized cerebral arteries from TBI rats exhibited greater myogenic tone at 60 mmHg and a diminished response to iberiotoxin, a BK channel pore blocker. In conclusion, moderately‐severe TBI enhances cerebral artery contractility, in part, through reductions in arterial myocyte BK channel subunit expression and function. Moreover, these TBI‐induced alterations in cerebral artery function can persist well beyond the initial 24–48 hour period post‐injury.Support or Funding InformationFlorida State UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Thyroid Hormone Deficiency Adversely Affects Cardiomyocyte T‐tubule Structure and Function
Authors: Zolotareva Natalie , Weick Rose‐Ann , An Shimin , Lee Jae S. , Zhang Youhua , Gerdes A. Martin , Ojamaa Kaie 
Published: June 2021

Thyroid hormone deficiency causes adverse changes in cardiomyocyte shape leading to increased wall stress, chamber dilatation and in the long‐term can result in heart failure. We hypothesized that thyroid hormones regulate cardiac contractile function in part by maintaining T‐tubule (TT) structures and efficient excitation‐contraction (EC)‐coupling.MethodsFemale Sprague‐Dawley rats (aged 12 wks) were surgically thyroidectomized (Tx) or were maintained as euthyroid (Eu) controls (6 rats/group). The study was terminated after 12 mo. at which time echocardiographic and hemodynamic measurements were recorded. Ventricular myocytes were isolated by collagenase digestion and plated onto laminin‐coated glass coverslips for TT analysis or were analyzed immediately for contractile and calcium dynamic using videobased edge detection of sarcomere length changes coupled to a fluorescence imaging system (IonOptix). Live cells were labeled with wheat germ agglutinin‐coupled to Alexa‐Fluor (WGA‐488) to image the sarcolemma and TT by confocal microscopy. Multiple z‐stack images were captured per cell and TT periodicity was analyzed using an algorithm to calculate periodicity based on the peak amplitude in the Fourier spectrum of the image at the TT frequency, or TT power. This software program is available as TTorg plugin on ImageJ.ResultsEchocardiography and in vivo hemodynamic measurements showed significantly reduced systolic and diastolic function in Tx vs euthyroid rats. In response to 1 Hz field stimulation at 4V, isolated cardiomyocyte contractile cycles showed significant dysfunction in Tx vs Eu cardiomyocytes: slower max contraction velocity (+Vmax), −2.047±0.30 vs −3.503±0.50 um/sec, Tx vs Eu, respectively, p<0.001; slower max relaxation velocity (‐Vmax), 1.369±0.27 vs 2.44±0.73 um/sec, p<0.01; longer time to peak contraction, 0.279±0.03 vs 0.182±0.03 sec, p<0.001. Myocytes were loaded with Fura2/AM (1uM) and intracellular calcium measured by fluorescence intensity ratio at 340/380 nm. Ca2+ transients showed slower kinetics in Tx vs Eu cardiomyocytes: time to Ca2+ peak, 0.076±0.01 vs 0.0516±0.003 sec, Tx vs Eu, respectively, p<0.0001; time to Ca2+ max return velocity, 0.261 0.03 vs 0.184 0.005, Tx vs Eu, respectively, p<0.0001. TTorg analysis indicated significant disorganization of T‐tubules in Tx cardiomyocytes compared to Eu (TT power = 61±2 vs 80±2, Tx vs Eu, respectively, p<0.00001; arbitrary units with higher values indicate increased periodicity). In conclusion, TH‐deficiency disrupts T‐tubule structures causing cardiomyocyte contractile dysfunction and slower calcium kinetics indicating altered EC‐coupling. Therefore maintaining normal thyroid function is necessary for optimal heart health.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.