Abstract 79: Sarcospan Has a Protective Effect During Development of Cardiac Disease

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Michelle S Parvatiyar ◽  
Reginald T Nguyen ◽  
Maria C Jordan ◽  
Kenneth P Roos ◽  
Rachelle H Crosbie-Watson
Keyword(s):  
Cell Adhesion ◽  
Cardiac Tissue ◽  
Physiological Function ◽  
Wall Stress ◽  
Muscle Dysfunction ◽  
Wild Type ◽  
Aortic Constriction ◽  
Muscle Histology ◽  
Cardiomyocyte Survival ◽  
Laminin Binding

Sarcospan (SSPN) has an important role in stabilizing sarcolemmal dystrophin- and utrophin-glycoprotein adhesion complexes at the cell membrane. Loss of cell adhesion leads to contraction-induced muscle damage, causing muscle dysfunction and cell death. Recently we have shown a specific role for SSPN in modulating cardiac cell adhesion and physiological function. After transthoracic aortic constriction (TAC), SSPN-null mice transitioned toward failure faster than wild-type (WT) mice. Muscle histology revealed large focal areas of collagen deposition in SSPN-null hearts after TAC compared to WT hearts, suggesting that increased membrane fragility affected cardiomyocyte survival. Our laboratory has shown that SSPN loss reduces sarcolemmal dystrophin levels and associated adhesion complexes in the heart. Whereas, the complete loss of dystrophin leads to development of Duchenne muscular dystrophy (DMD), causing cardiac dysfunction and early mortality. Overexpression of SSPN in DMD mice increased cell adhesion and laminin binding in hearts, leading to improvements in tissue histopathology and increased expression of utrophin, a functional homologue of dystrophin. Examining the restorative potential of SSPN in dystrophic cardiac tissue, led us to query whether compensatory upregulation of SSPN occurs in failing hearts of TAC-treated WT mice. In failing non-DMD hearts, we found that SSPN expression is increased. We have evidence of a chaperone role for SSPN, and its increased expression in the failing heart may contribute to the increased localization of dystrophin and associated glycoprotein complexes at the sarcolemma, which we observed in failing WT hearts compared to untreated controls. The upregulation of cell-stabilizing cell adhesion complexes may compensate for increased wall stress and counter pathological processes that culminate in cardiomyocyte demise, and we are exploring whether naturally increased expression or transgenic overexpression of SSPN in the heart may protect against damage. In summary, we have found that SSPN promotes cardiac function by maintaining cell adhesion and promoting cell survival during disease conditions.

scholarly journals Local Action of Neprilysin Exacerbates Pressure Overload Induced Cardiac Remodeling

Hypertension ◽  
2021 ◽  
Author(s):  
Hitoshi Nakagawa ◽  
Takuya Kumazawa ◽  
Kenji Onoue ◽  
Yasuki Nakada ◽  
Tomoya Nakano ◽  
...  
Keyword(s):  
Natriuretic Peptides ◽  
Cardiac Tissue ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Heart Weight ◽  
Wild Type ◽  
Aortic Constriction ◽  
Heart Failure Treatment ◽  
Hypertrophic Response

NEP (Neprilysin) degrades natriuretic peptides, and its inhibition is a clinically accepted target for heart failure treatment. NEP is widely expressed in various organs, including the heart. However, the pathophysiological significance of local cardiac NEP is not fully understood. To study the local function of NEP in the heart, we generated transgenic mice overexpressing NEP, specifically in cardiomyocytes (CM-NEP Tg). At baseline, CM-NEP Tg mice showed significantly lower levels of plasma ANP (atrial natriuretic peptide), plasma cGMP, and cardiac tissue cGMP versus wild-type (WT) mice. Blood pressure, heart weight, and cardiomyocyte diameter were greater in CM-NEP Tg than WT mice. There were no significant differences in interstitial fibrosis or ejection fraction. Transverse aortic constriction (TAC) surgery significantly increased left ventricular weight in WT and CM-NEP Tg mice 3 weeks post-op versus sham surgery; however, the cardiac hypertrophic response to TAC was higher in CM-NEP Tg than WT mice. Cardiac interstitial fibrosis was induced in TAC CM-NEP Tg mice, whereas TAC WT mice had none. TAC CM-NEP Tg, but not TAC WT, mice developed cardiac dysfunction secondary to TAC with echocardiography. Furthermore, administration of human ANP to raise plasma ANP levels comparable to those in WT mice neither improved the exacerbated cardiac hypertrophy and fibrosis nor recovered impaired cardiac function in CM-NEP Tg mice after TAC. In conclusion, overexpression of NEP in cardiomyocytes promoted degradation of natriuretic peptides in the heart and led to an exaggerated response of hypertrophy and fibrosis to pressure overload.

scholarly journals Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ritu Pandey ◽  
Muhan Zhou ◽  
Shariful Islam ◽  
Baowei Chen ◽  
Natalie K Barker ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Therapeutic Target ◽  
Cell Activity ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Ductal Adenocarcinoma ◽  
Wild Type ◽  
Cancer Genome Atlas ◽  
Novel Therapeutic

AbstractWe investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6−/− cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

Dissociation between alveolar transmigration of neutrophils and lung injury in hyperoxia

2006 ◽  
Vol 291 (5) ◽  
pp. L1050-L1058 ◽  
Author(s):  
Sandra Perkowski ◽  
Arnaud Scherpereel ◽  
Juan-Carlos Murciano ◽  
Evguenia Arguiri ◽  
Charalambos C. Solomides ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Lung Injury ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Wild Type ◽  
Pulmonary Endothelium ◽  
Pulmonary Uptake ◽  
Endothelial Surface ◽  
Platelet Endothelial Cell Adhesion ◽  
Cell Adhesion Molecule 1

The objective of this study was to quantitatively assess changes in cell adhesion molecule (CAM) expression on the pulmonary endothelial surface during hyperoxia and to assess the functional significance of those changes on cellular trafficking and development of oxygen-induced lung injury. Mice were placed in >95% O2 for 0–72 h, and pulmonary injury and neutrophil (PMN) sequestration were assessed. Specific pulmonary CAM expression was quantified with a dual-radiolabeled MAb technique. To test the role of CAMs in PMN trafficking during hyperoxia, blocking MAbs to murine P-selectin, ICAM-1, or platelet-endothelial cell adhesion molecule-1 (PECAM-1) were injected in wild-type mice. Mice genetically deficient in these CAMs and PMN-depleted mice were also evaluated. PMN sequestration occurred within 8 h of hyperoxia, although alveolar emigration occurred later (between 48 and 72 h), coincident with rapid escalation of the lung injury. Hyperoxia significantly increased pulmonary uptake of radiolabeled antibodies to P-selectin, ICAM-1, and PECAM-1, reflecting an increase in their level on pulmonary endothelium and possibly sequestered blood cells. Although both anti-PECAM-1 and anti-ICAM-1 antibodies suppressed PMN alveolar influx in wild-type mice, only mice genetically deficient in PECAM-1 showed PMN influx suppression. Neither CAM blockade, nor genetic deficiency, nor PMN depletion attenuated lung injury. We conclude that early pulmonary PMN retention during hyperoxia is not temporally associated with an increase in endothelial CAMs; however, subsequent PMN emigration into the alveolar space may be supported by PECAM-1 and ICAM-1. Blocking PMN recruitment did not prevent lung injury, supporting dissociation between PMN infiltration and lung injury during hyperoxia in mice.

scholarly journals Receptor functions for the integrin VLA-3: fibronectin, collagen, and laminin binding are differentially influenced by Arg-Gly-Asp peptide and by divalent cations.

1991 ◽  
Vol 112 (1) ◽  
pp. 169-181 ◽  
Author(s):  
M J Elices ◽  
L A Urry ◽  
M E Hemler
Keyword(s):  
Cell Adhesion ◽  
Divalent Cations ◽  
Small Cell Lung Carcinoma ◽  
Rgd Peptide ◽  
Dependent Manner ◽  
Cell Lung Carcinoma ◽  
Ligand Affinity ◽  
Rgd Site ◽  
Inhibition Studies ◽  
Laminin Binding

The capability of the integrin VLA-3 to function as a receptor for collagen (Coll), laminin (Lm), and fibronectin (Fn) was addressed using both whole cell adhesion assays and ligand affinity columns. Analysis of VLA-3-mediated cell adhesion was facilitated by the use of a small cell lung carcinoma line (NCI-H69), which expresses VLA-3 but few other integrins. While VLA-3 interaction with Fn was often low or undetectable in cells having both VLA-3 and VLA-5, NCI-H69 cells readily attached to Fn in a VLA-3-dependent manner. Both Arg-Gly-Asp (RGD) peptide inhibition studies, and Fn fragment affinity columns suggested that VLA-3, like VLA-5, may bind to the RGD site in human Fn. However, unlike Fn, both Coll and Lm supported VLA-3-mediated adhesion that was not inhibited by RGD peptide, and was totally unaffected by the presence of VLA-5. In addition, VLA-3-mediated binding to Fn was low in the presence of Ca++, but was increased 6.6-fold with Mg++, and 30-fold in the presence of Mn++. In contrast, binding to Coll was increased only 1.2-fold with Mg++, and 1.7-fold in Mn++, as compared to the level seen with Ca++. Together, these experiments indicate that VLA-3 can bind Coll, Lm, and Fn, and also show that (a) VLA-3 can recognize both RGD-dependent and RGD-independent ligands, and (b) different VLA-3 ligands have distinctly dissimilar divalent cation sensitivities.

scholarly journals Direct biologically based biosensing of dynamic physiological function

2001 ◽  
Vol 280 (5) ◽  
pp. H2006-H2010 ◽  
Author(s):  
David J. Christini ◽  
Jeff Walden ◽  
Jay M. Edelberg
Keyword(s):  
Real Time ◽  
Cardiac Tissue ◽  
Physiological Function ◽  
Physiological Activity ◽  
Functional Integration ◽  
Dynamic Regulation ◽  
Excitable Tissue ◽  
Alternative Approach

Dynamic regulation of biological systems requires real-time assessment of relevant physiological needs. Biosensors, which transduce biological actions or reactions into signals amenable to processing, are well suited for such monitoring. Typically, in vivo biosensors approximate physiological function via the measurement of surrogate signals. The alternative approach presented here would be to use biologically based biosensors for the direct measurement of physiological activity via functional integration of relevant governing inputs. We show that an implanted excitable-tissue biosensor (excitable cardiac tissue) can be used as a real-time, integrated bioprocessor to analyze the complex inputs regulating a dynamic physiological variable (heart rate). This approach offers the potential for long-term biologically tuned quantification of endogenous physiological function.

scholarly journals Complement factor D is linked to platelet activation in human and rodent sepsis

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
O. Sommerfeld ◽  
K. Dahlke ◽  
M. Sossdorf ◽  
R. A. Claus ◽  
A. Scherag ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Physiological Function ◽  
Plasma Concentrations ◽  
Cecal Ligation ◽  
Clinical Importance ◽  
Surface Expression ◽  
Antiplatelet Drugs ◽  
Complement Factor ◽  
Wild Type ◽  
Deficient Mice

Abstract Background The complement factor D (CFD) exerts a regulatory role during infection. However, its physiological function in coagulopathy and its impact on the course of an infection remains unclear. Materials Wild-type and CFD-deficient mice (n = 91) were subjected to cecal ligation and puncture to induce sepsis. At several time points, markers of coagulation and the host-immune response were determined. Furthermore, in patients (n = 79) with sepsis or SIRS, CFD levels were related to clinical characteristics, use of antiplatelet drugs and outcome. Results Septic CFD-deficient mice displayed higher TAT complexes (p = 0.02), impaired maximal clot firmness, but no relevant platelet drop and reduced GPIIb/IIIa surface expression on platelets (p = 0.03) compared to septic wild-type mice. In humans, higher CFD levels (non-survivors, 5.0 µg/ml to survivors, 3.6 µg/ml; p = 0.015) were associated with organ failure (SOFA score: r = 0.33; p = 0.003) and mortality (75% percentile, 61.1% to 25% percentile, 26.3%). CFD level was lower in patients with antiplatelet drugs (4.5–5.3 µg/ml) than in patients without. Conclusion In mice, CFD is linked to pronounced platelet activation, depicted by higher GPIIb/IIIa surface expression in wild-type mice. This might be of clinical importance since high CFD plasma concentrations were also associated with increased mortality in sepsis patients.

scholarly journals A fragment of cell adhesion molecule L1 reduces amyloid-β plaques in a mouse model of Alzheimer’s disease

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Junkai Hu ◽  
Stanley Li Lin ◽  
Melitta Schachner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Wild Type ◽  
Model Of Alzheimer’S Disease ◽  
Cell Adhesion Molecule L1

AbstractDeposition of amyloid-β (Aβ) in the brain is one of the important histopathological features of Alzheimer’s disease (AD). Previously, we reported a correlation between cell adhesion molecule L1 (L1) expression and the occurrence of AD, but its relationship was unclear. Here, we report that the expression of L1 and a 70 kDa cleavage product of L1 (L1-70) was reduced in the hippocampus of AD (APPswe) mice. Interestingly, upregulation of L1-70 expression in the hippocampus of 18-month-old APPswe mice, by parabiosis involving the joining of the circulatory system of an 18-month-old APPswe mouse with a 2-month-old wild-type C57BL/6 mouse, reduced amyloid plaque deposition. Furthermore, the reduction was accompanied by the appearance of a high number of activated microglia. Mechanistically, we observed that L1-70 could combine with topoisomerase 1 (Top1) to form a complex, L1-70/Top1, that was able to regulate expression of macrophage migration inhibitory factor (MIF), resulting in the activation of microglia and reduction of Aβ plaques. Also, transforming growth factor β1 (TGFβ-1) transferred from the blood of young wild-type C57BL/6 mice to the aged AD mice, was identified as a circulating factor that induces full-length L1 and L1-70 expression. All together, these findings suggest that L1-70 contributes to the clearance of Aβ in AD, thereby adding a novel perspective in understanding AD pathogenesis.

Abstract 110: Thrombospondin Type-1 Domain-Containing Protein 1 (THSD1), an Intracranial Aneurysm Susceptibility Gene, Mediates Cell Adhesion in Human Umbilical Vein Endothelial Cells

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Xiaoqian Fang ◽  
Dong H Kim ◽  
Teresa Santiago-Sim
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
Focal Adhesion ◽  
Umbilical Vein ◽  
Adhesion Formation ◽  
Wild Type ◽  
Focal Adhesion Formation ◽  
Umbilical Vein Endothelial Cells

Introduction: An intracranial aneurysm (IA) is a weak spot in cerebral blood vessel wall that can lead to its abnormal bulging. Previously, we reported that mutations in THSD1 , encoding thrombospondin type-1 domain-containing protein 1, are associated with IA in a subset of patients. THSD1 is a transmembrane molecule with a thrombospondin type-1 repeat (TSR). Proteins with TSR domain have been implicated in a variety of processes including regulation of matrix organization, cell adhesion and migration. We have shown that in mouse brain Thsd1 is expressed in endothelial cells. Hypothesis: THSD1 plays an important role in maintaining the integrity of the endothelium by promoting adhesion of endothelial cells to the underlying basement membrane. Methods: Human umbilical vein endothelial cells are used to investigate the role of THSD1 in vitro . THSD1 expression was knocked-down by RNA interference. Cell adhesion assay was done on collagen I-coated plates and focal adhesion formation was visualized using immunofluorescence by paxillin and phosphorylated focal adhesion kinase (pFAK) staining. THSD1 re-expression is accomplished by transfection with a pCR3.1-THSD1-encoding plasmid. Results: Knockdown of THSD1 caused striking change in cell morphology and size. Compared to control siRNA-treated cells that exhibited typical cobblestone morphology, THSD1 knockdown cells were narrow and elongated, and were significantly smaller ( p <0.01). Cell adherence to collagen I-coated plates was also attenuated in THSD1 knockdown cells ( p <0.01). Consistent with this finding is the observation that the number and size of focal adhesions, based on paxillin and pFAK staining, were significantly reduced after THSD1 knockdown ( p <0.01). These defects in cell adhesion and focal adhesion formation were rescued by re-expression of wild type THSD1 ( p <0.05). In contrast, initial studies indicate that expression of mutated versions of THSD1 as seen in human patients (L5F, R450*, E466G, P639L) could not restore cell adhesion and focal adhesion formation to wild type levels. Conclusions: Our studies provide evidence for a role of THSD1 and THSD1 mutations in endothelial cell adhesion and suggest a possible mechanism underlying THSD1 -mediated aneurysm disease.

Abstract 338: Cardiac Overexpression of Creatine Kinase Improves Cardiomycytes Function in Heart Failure and During Increased Redox Stress

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Carlo G Tocchetti ◽  
Michelle Leppo ◽  
Djahida Bedja ◽  
Yibin Wang ◽  
Robert G Weiss ◽  
...  
Keyword(s):  
Heart Failure ◽  
Myocardial Dysfunction ◽  
Similar Response ◽  
Wild Type ◽  
Aortic Constriction ◽  
Redox Stress ◽  
Adult Cardiomyocytes ◽  
Metabolic Role ◽  
Myocyte Function ◽  
Fractional Shortening

Aims: Several studies suggest that abnormal energy metabolism contributes to heart failure or that the failing heart is energy starved. Here we aim at testing whether an increase in intracellular CK improves myocellular contractility in experimental myocardial dysfunction and protects from increased oxidative conditions. Methods-Results: We tested the response to the β-agonist isoproterenol (2.5 nM, ISO) in field-stimulated (.5 Hz, RT) adult cardiomyocytes isolated from wild-type (WT) mice and mice overexpressing cardiac myofibrillar or mitochondrial CK (CK-M or CK-mito) from sham and failing (8 wk transverse aortic constriction (TAC)) hearts, to dissect whether overexpressing CK alters myocyte function at baseline and during increased energetic demand. There were no differences in sarcomere fractional shortening (FS) or Ca2+ transients at baseline and with ISO among sham WT, CK-M or CK-mito myocytes. However, ISO effects were significantly reduced in WT TAC myocytes, consistent with prior reports. Conversely, in CK-M or CK-mito TAC myocytes, ISO-induced inotropy was fully preserved. Interestingly, incubation with the AMPK-stimulator AICAR (1mM for at least 90’) did not have any effect on WT TAC, but increased FS in TAC CK-M (+82%) and CK-mito (+42%) myocytes significantly, supporting the important metabolic role played by enhancing CK in failing hearts. To test whether overexpressing CK-M or CK-mito confer protection against acute oxidative stress, sham myocytes were exposed to H2O2 (50μM, 10’) and the interval (seconds) between the beginning of H2O2 superfusion and the appearance of irreversible arrhythmias was measured. WT and CK-M myocytes had a similar response (416±91s vs 411±68s), whereas in CK-mito this interval was significantly prolonged (600±64s). Similarly, upon acute infusion of the anticancer TKI sunitinib (2μM), whose cardiotoxic properties have been linked also to an increase in ROS, irreversible arrhythmias appeared after 657±43s in CK-mito (p<.5 vs 561±66 for WT and 467±88 for CK-M). Conclusions: Overexpressing CK-M and CK-mito under failing-TAC conditions improves myocyte function likely through better preserved Ca2+ handling, whereas only the up-regulation of CK-mito is more effective in buffering ROS effects.

Abstract 361: Creg1 Interacts With Sec8 to Promote Cell-cell Adhesion During Cardiomyogenesis

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Jie Liu ◽  
Yanmei Qi ◽  
Shu-Chan Hsu ◽  
Siavash Saadat ◽  
Saum Rahimi ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Es Cells ◽  
Embryonic Stem ◽  
Intercellular Junctions ◽  
Amino Acid Residues ◽  
Loss Of Function ◽  
Wild Type ◽  
Adhesion Sites ◽  
Cell Cell

Cellular repressor of E1A-stimulated genes 1 (CREG1) is a 24 kD glycoprotein essential for early embryonic development. Our immunofluorescence studies revealed that CREG1 is highly expressed at myocyte junctions in both embryonic and adult hearts. To explore it role in cardiomyogenesis, we employed gain- and loss-of-function analyses demonstrating that CREG1 is required for the differentiation of mouse embryonic stem (ES) cell into cohesive myocardium-like structures. Chimeric cultures of wild-type and CREG1 knockout ES cells expressing cardiac-specific reporters showed that the cardiomyogenic effect of CREG1 is cell autonomous. Furthermore, we identified a novel interaction between CREG1 and Sec8 of the exocyst complex, which tethers vesicles to the plasma membrane. Mutations of the amino acid residues D141 and P142 to alanine in CREG1 abolished its binding to Sec8. To address the role of the CREG1-Sec8 interaction in cardiomyogenesis, we rescued CREG1 knockout ES cells with wild-type and Sec8-binding mutant CREG1 and showed that CREG1 binding to Sec8 promotes cardiomyocyte differentiation and cohesion. Mechanistically, CREG1, Sec8 and N-cadherin all localize at cell-cell adhesion sites. CREG1 overexpression enhances the assembly of adherens and gap junctions. By contrast, its knockout inhibits the Sec8-N-cadherin interaction and induces their degradation. Finally, shRNA-mediated knockdown of Sec8 leads to cardiomyogenic defects similar to CREG1 knockout. These results suggest that the CREG1 binding to Sec8 enhances the assembly of intercellular junctions and promotes cardiomyogenesis.

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