Abstract 654: Loss of SPRR3 In ApoE -/- Mice Leads to Increased Atheroma Vulnerability and Evidence of Plaque Rupture and Cardiac Infarcts

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Amanda K Segedy ◽  
Bin Li ◽  
Caressa D Lietman ◽  
MacRae F Linton ◽  
Pampee P Young
Keyword(s):  
Myocardial Infarction ◽  
Plaque Rupture ◽  
Experimental Studies ◽  
Intraplaque Hemorrhage ◽  
Type I ◽  
Gelatinase Activity ◽  
Plaque Instability ◽  
Atherosclerosis Progression

Atheroma rupture is the leading cause of myocardial infarction. While studies have examined inflammatory cell-mediated effects on plaque vulnerability, less is known about the role of vascular smooth muscle cells (VSMCs) or specific molecular players in the maintenance of atheroma stability. We reported that loss of small proline-rich repeat protein 3 (SPRR3), enriched in atheroma VSMCs, leads to increased VSMC death and significantly accelerates atherosclerosis progression in ApoE -/- mice. Here, we show that loss of SPRR3 promotes features in plaques of brachiocephalic arteries common to unstable lesions, such as increased necrotic core size, reduced cap collagen content, and reduced VSMC content. Moreover, ApoE -/- mice lacking SPRR3 develop coronary artery lesions with advanced features, including intraplaque hemorrhage. In addition, Sprr3 -/- ApoE -/- mice fed a high-fat diet for 6 months develop spontaneous myocardial infarction. In vitro , SPRR3 deficient VSMCs show reduced expression of procollagen type I, an event associated with Akt activation. SPRR3-deficient VSMCs also show increased expression of MMP2 transcripts, and aortic root lesions of Sprr3 -/- ApoE -/- mice have increased gelatinase activity consistent with MMP2 activation. Our data demonstrate that SPRR3 loss in ApoE -/- mice decreases VSMC survival and collagen I synthesis while increasing MMP2 synthesis and activity, resulting in atheroma instability with evidence of downstream myocardial infarction. Taken together the results present the Sprr3 -/- ApoE -/- mouse as an experimental model of plaque rupture. This model will be used for additional experimental studies including in vivo genetic modulation of the Akt pathway as well as in vitro studies to determine phenotypic outcome, i.e. coronary arterial lesions, myocardial infarction, VSMC survival and collagen synthesis. We hope to establish a mechanistic link between altered Akt signaling and matrix integrity in the context of atheroma rupture, as well as potentially use SPRR3 as a molecular marker which could lead to detection of plaque instability as well as therapeutic intervention methodologies.

scholarly journals bFGF blockade reduces intraplaque angiogenesis and macrophage infiltration in atherosclerotic vein graft lesions in ApoE3*Leiden mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Laura Parma ◽  
Hendrika A. B. Peters ◽  
Thijs J. Sluiter ◽  
Karin H. Simons ◽  
Paolo Lazzari ◽  
...  
Keyword(s):  
Femoral Artery ◽  
Plaque Rupture ◽  
Thrombus Formation ◽  
Tube Formation ◽  
Macrophage Infiltration ◽  
Intraplaque Hemorrhage ◽  
Vein Grafts ◽  
Matrigel Plug

Abstract Intraplaque angiogenesis increases the chance of unstable atherosclerotic plaque rupture and thrombus formation leading to myocardial infarction. Basic Fibroblast Growth Factor (bFGF) plays a key role in angiogenesis and inflammation and is involved in the pathogenesis of atherosclerosis. Therefore, we aim to test K5, a small molecule bFGF-inhibitor, on remodelling of accelerated atherosclerotic vein grafts lesions in ApoE3*Leiden mice. K5-mediated bFGF-signalling blockade strongly decreased intraplaque angiogenesis and intraplaque hemorrhage. Moreover, it reduced macrophage infiltration in the lesions by modulating CCL2 and VCAM1 expression. Therefore, K5 increases plaque stability. To study the isolated effect of K5 on angiogenesis and SMCs-mediated intimal hyperplasia formation, we used an in vivo Matrigel-plug mouse model that reveals the effects on in vivo angiogenesis and femoral artery cuff model to exclusively looks at SMCs. K5 drastically reduced in vivo angiogenesis in the matrigel plug model while no effect on SMCs migration nor proliferation could be seen in the femoral artery cuff model. Moreover, in vitro K5 impaired endothelial cells functions, decreasing migration, proliferation and tube formation. Our data show that K5-mediated bFGF signalling blockade in hypercholesterolemic ApoE3*Leiden mice reduces intraplaque angiogenesis, haemorrhage and inflammation. Therefore, K5 is a promising candidate to stabilize advanced atherosclerotic plaques.

Abstract 413: Podoplanin Neutralization Improves Cardiac Remodeling and Function After Acute Myocardial Infarction

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Maria Cimini ◽  
Venkata N Garikipati ◽  
Suresh K Verma ◽  
Cindy Benedict ◽  
Zhongjian Cheng ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Remodeling ◽  
Magnetic Beads ◽  
Neutralizing Antibody ◽  
Treated Group ◽  
Border Zone ◽  
Control Group ◽  
Type I

Variety of cardioprotective and reparative therapeutic approaches have emerged for the treatment of cardiac remodeling after myocardial infarction (MI). Here we propose a novel mechanism using a neutralizing antibody that target Podoplanin (PDPN), a platelet aggregation-inducing type I transmembrane glycoprotein, expressed on a cohort of myocardial cells that migrate to the infarcted area after MI and contribute significantly to scar formation. The PDPN+ cells were isolated from infarcted hearts two days after MI, using magnetic beads sorting. We tested in vitro the effect of PDPN neutralizing antibody (5μg/ml) in a transwell migration assay and the activation of monocytes co-cultured with PDPN+ cells. The neutralizing antibody decreased significantly PDPN+ cells migration. Monocytes co-cultured with PDPN+ cells produced high levels of IL1α and IL12, whereas treatment of co-cultures with podoplanin neutralizing antibody inhibited IL1α and IL12 production and increased IL9 and IL10 production, suggesting a switch form pro-inflammatory to anti-inlammatory phenotype. To tests the effect of podoplanin neutralizing antibody in vivo, C57BL/6 wild type mice were subjected to experimental MI and anti-PDPN antibody (25μg/ml) was injected i.p. on days 1, 2, 7 and 15 after MI and mice were scarified two months after. At 7 days after MI echocardiography revealed comparable ~30% of ejection fraction (EF) in control and antibody-injected mice. After one month EF% remained unchanged in control group and increased up to 45% in antibody-treated group, suggesting improvement in cardiac function. Histologically, in the control group the ischemic area was composed by fibrotic tissue highly positive for fibronectin and αSMA, whereas in the antibody-treated group revealed large number of survived, as well as proliferating myocytes expressing αSARC-actin and Phospho-H3. Further, there was a significant increase in CD31 positive cells in the infarct border-zone of antibody-treated vs. control hearts, suggesting increased angiogenesis. Our findings suggest that inhibition of PDPN during first two weeks after MI intensely enhances cardiac regeneration and angiogenesis. This may represent a new therapeutic support for the tissue renewal after MI.

scholarly journals Triple, Mutually Orthogonal Cycloadditions Through the Design of Electronically Activated SNO-OCTs

2020 ◽  
Author(s):  
Yun Hu ◽  
Jessica M. Roberts ◽  
Henry R. Kilgore ◽  
Amirah Mat Lani ◽  
Ronald Raines ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Experimental Studies ◽  
Order Rate Constant ◽  
Cell Labeling ◽  
Type I ◽  
Electronic Tuning ◽  
Live Cell Labeling ◽  
New Compounds

Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds capable of fast and predictable reactions. The ability to easily modify heterocyclic strained cyclooctynes containing sulfamate backbones (SNO-OCTs) enables electronic tuning of the relative rates of reactions of SNO-OCTs in cycloadditions with Type I–III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant rate enhancements for reactions of a difluorinated SNO-OCT derivative compared to the parent scaffold were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 1 M−1 s −1 . Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications.

scholarly journals Weighted Gene Co-Expression Network Analysis Combined with Machine Learning Validation to Identify Key Modules and Hub Genes Associated with SARS-CoV-2 Infection

2021 ◽  
Vol 10 (16) ◽  
pp. 3567
Author(s):  
Hassan Karami ◽  
Afshin Derakhshani ◽  
Mohammad Ghasemigol ◽  
Mohammad Fereidouni ◽  
Ebrahim Miri-Moghaddam ◽  
...  
Keyword(s):  
Network Analysis ◽  
Signaling Pathway ◽  
Drug Targets ◽  
Experimental Studies ◽  
A549 Cells ◽  
Enrichment Analysis ◽  
Type I ◽  
Hub Genes

The coronavirus disease-2019 (COVID-19) pandemic has caused an enormous loss of lives. Various clinical trials of vaccines and drugs are being conducted worldwide; nevertheless, as of today, no effective drug exists for COVID-19. The identification of key genes and pathways in this disease may lead to finding potential drug targets and biomarkers. Here, we applied weighted gene co-expression network analysis and LIME as an explainable artificial intelligence algorithm to comprehensively characterize transcriptional changes in bronchial epithelium cells (primary human lung epithelium (NHBE) and transformed lung alveolar (A549) cells) during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our study detected a network that significantly correlated to the pathogenicity of COVID-19 infection based on identified hub genes in each cell line separately. The novel hub gene signature that was detected in our study, including PGLYRP4 and HEPHEL1, may shed light on the pathogenesis of COVID-19, holding promise for future prognostic and therapeutic approaches. The enrichment analysis of hub genes showed that the most relevant biological process and KEGG pathways were the type I interferon signaling pathway, IL-17 signaling pathway, cytokine-mediated signaling pathway, and defense response to virus categories, all of which play significant roles in restricting viral infection. Moreover, according to the drug–target network, we identified 17 novel FDA-approved candidate drugs, which could potentially be used to treat COVID-19 patients through the regulation of four hub genes of the co-expression network. In conclusion, the aforementioned hub genes might play potential roles in translational medicine and might become promising therapeutic targets. Further in vitro and in vivo experimental studies are needed to evaluate the role of these hub genes in COVID-19.

scholarly journals Transcriptional analysis of lung epithelial cells using WGCNA revealed the role of IRF9 and IFI6 genes in SARS-CoV-2 pathogenicity

2020 ◽  
Author(s):  
Hassan Karami ◽  
Afshin Derakhshani ◽  
Mohammad Fereidouni ◽  
Ebrahim Miri-Moghaddam ◽  
Behzad Baradaran ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Experimental Studies ◽  
A549 Cells ◽  
Lung Epithelial Cells ◽  
Transcriptional Analysis ◽  
Type I ◽  
Hub Genes

Abstract The coronavirus disease 2019 (COVID-19) outbreak is an ongoing global health emergence, but the pathogenesis remains unclear. Here, we applied weighted gene co-expression network analysis to comprehensively characterize transcriptional changes in bronchial epithelium cells (NHBE and A549 cells) during SARS-CoV-2 infection. Our analysis identified a network highly correlated to COVID-19 pathogenicity based on MX1, IFIT1, ISG15, IFI6, DDX60, IRF9, PARP9, PGLYRP4, IL36G, SAA2 and IL-8 hub genes. The results also indicated a unique transcriptional signatures of infected cells including IFI6 and IRF9 as novel gene candidates and suggested their prospective mechanism in COVID-19 pathogenesis. The result of hub genes enrichment showed that the most correlation topic in biological process and KEGG were type I interferon signaling pathway, IL-17 signaling pathway, cytokine mediated signaling pathway, and defense response to virus categories which all play significant roles in restricting viral infection. Also according to the drug-target network, we recognized 54 FDA-approved drug candidates for other indications could potentially use for the treatment of COVID-19 patients through regulation of six hub genes of the co-expression network. Our findings also showed that the 19 experimentally validated miRNAs regulated the co-expression network through 5 hub genes (SLC19A3, FAM13A, PLA2G16, and HRASLS5). In conclusion, these hub genes had potential roles in the translational medicine and might become promising therapeutic targets further in vitro and in vivo experimental studies are needed to evaluate the role of above mentioned genes in COVID-19.

scholarly journals Triple, Mutually Orthogonal Cycloadditions Through the Design of Electronically Activated SNO-OCTs

2020 ◽  
Author(s):  
Yun Hu ◽  
Jessica M. Roberts ◽  
Henry R. Kilgore ◽  
Amirah Mat Lani ◽  
Ronald Raines ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Experimental Studies ◽  
Order Rate Constant ◽  
Cell Labeling ◽  
Type I ◽  
Electronic Tuning ◽  
Live Cell Labeling ◽  
New Compounds

Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds capable of fast and predictable reactions. The ability to easily modify heterocyclic strained cyclooctynes containing sulfamate backbones (SNO-OCTs) enables electronic tuning of the relative rates of reactions of SNO-OCTs in cycloadditions with Type I–III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant rate enhancements for reactions of a difluorinated SNO-OCT derivative compared to the parent scaffold were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 1 M−1 s −1 . Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications.

Clinical Trials in Thrombosis: Secondary Prevention of Myocardial Infarction

1976 ◽  
Vol 35 (01) ◽  
pp. 049-056 ◽  
Author(s):  
Christian R Klimt ◽  
P. H Doub ◽  
Nancy H Doub
Keyword(s):  
Myocardial Infarction ◽  
Secondary Prevention ◽  
Case Control ◽  
Therapeutic Effects ◽  
Case Control Studies ◽  
Definitive Answer ◽  
Inhibition Of Platelet Aggregation ◽  
Prospective Trials

SummaryNumerous in vivo and in vitro experiments, investigating the inhibition of platelet aggregation and the prevention of experimentally-induced thrombosis, suggest that anti-platelet drugs, such as aspirin or the combination of aspirin and dipyridamole or sulfinpyrazone, may be effective anti-thrombotic agents in man. Since 1971, seven randomized prospective trials and two case-control studies have been referenced in the literature or are currently being conducted, which evaluate the effects of aspirin, sulfinpyrazone, or dipyridamole in combination with aspirin in the secondary prevention of myocardial infarction. A critical review of these trials indicates a range of evidence from no difference to a favorable trend that antiplatelet drugs may serve as anti-thrombotic agents in man. To date, a definitive answer concerning the therapeutic effects of these drugs in the secondary prevention of coronary heart disease is not available.

Peculiarities of the course of type I allergic reactions in patients with blood diseases

2020 ◽  
pp. 40-50
Author(s):  
A. Nikitina
Keyword(s):  
Search Engines ◽  
Anaphylactic Shock ◽  
Type I ◽  
Allergic Reactions ◽  
Common Cause ◽  
Blood Diseases ◽  
Treatment Regimens ◽  
Modern Methods

Analysis of literature data presented in search engines — Elibrary, PubMed, Cochrane — concerning the risk of developing type I allergic reactions in patients with blood diseases is presented. It is shown that the most common cause of type I allergic reactions is drugs included in the treatment regimens of this category of patients. The article presents statistics on the increase in the number of drug allergies leading to cases of anaphylactic shock in patients with blood diseases. Modern methods for the diagnosis of type I allergic reactions in vivo and in vitro are considered.

scholarly journals Collagen-Based Electrospun Materials for Tissue Engineering: A Systematic Review

2021 ◽  
Vol 8 (3) ◽  
pp. 39
Author(s):  
Britani N. Blackstone ◽  
Summer C. Gallentine ◽  
Heather M. Powell
Keyword(s):  
Systematic Review ◽  
Tissue Engineering ◽  
Collagen Type I ◽  
The Body ◽  
Pool Data ◽  
Type I ◽  
High Concentrations ◽  
Increased Strength

Collagen is a key component of the extracellular matrix (ECM) in organs and tissues throughout the body and is used for many tissue engineering applications. Electrospinning of collagen can produce scaffolds in a wide variety of shapes, fiber diameters and porosities to match that of the native ECM. This systematic review aims to pool data from available manuscripts on electrospun collagen and tissue engineering to provide insight into the connection between source material, solvent, crosslinking method and functional outcomes. D-banding was most often observed in electrospun collagen formed using collagen type I isolated from calfskin, often isolated within the laboratory, with short solution solubilization times. All physical and chemical methods of crosslinking utilized imparted resistance to degradation and increased strength. Cytotoxicity was observed at high concentrations of crosslinking agents and when abbreviated rinsing protocols were utilized. Collagen and collagen-based scaffolds were capable of forming engineered tissues in vitro and in vivo with high similarity to the native structures.

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