Abstract 471: Influence of Platelet-specific Soluble Guanylyl Cyclase Deficiency on Atherosclerotic Plaque Formation

2018 ◽  
Vol 38 (Suppl_1) ◽  
Author(s):  
Marlène Stroth ◽  
Noomen Bettaga ◽  
Jana Wobst ◽  
Julia Werner ◽  
Anna-Sophia Zimmermann ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Plaque Formation ◽  
Atherosclerotic Plaque Formation

scholarly journals Loss of soluble guanylyl cyclase in platelets contributes to atherosclerotic plaque formation and vascular inflammation

2021 ◽  
Author(s):  
Carina Mauersberger ◽  
Hendrik B Sager ◽  
Jana Wobst ◽  
Tan An Dang ◽  
Laura Lambrecht ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Guanylyl Cyclase ◽  
Leukocyte Adhesion ◽  
Vascular Inflammation ◽  
Soluble Guanylyl Cyclase ◽  
Plaque Formation ◽  
Allele Carrier ◽  
Atherosclerotic Plaque Formation ◽  
Angiopoietin 1

Aim: The role of platelets in atherosclerosis remains incompletely understood. Variants in genes encoding the soluble guanylyl cyclase (sGC) in platelets are associated with coronary artery disease (CAD) risk. Here we sought to investigate the contribution of platelet sGC to atherosclerosis and the therapeutic potential of targeting sGC in atherosclerosis. Methods and Results: We genetically deleted sGC in platelets of atherosclerosis-prone Ldlr-/- mice. By intravital fluorescence microscopy such Pf4-Cre+Gucy1b1flox/floxLdlr-/- mice displayed enhanced leukocyte adhesion to atherosclerotic plaques in comparison with their litter mates. Moreover, histological and flow cytometry analyses revealed more numerous inflammatory leukocytes and larger plaque sizes in aortic tissue of Ldlr-/- mice lacking sGC in platelets. In vitro, supernatant from activated platelets lacking sGC promoted leukocyte adhesion to endothelial cells (EC) via enhanced EC activation. Using cytokine profiling, we identified reduced angiopoietin-1 release by Pf4-Cre+Gucy1b1flox/flox and human GUCY1A1 risk allele carrier platelets to be responsible for enhanced activation of EC and subsequent leukocyte adhesion. Pharmacological sGC stimulation increased platelet angiopoietin-1 release in vitro and reduced recruitment of adoptively transferred leukocytes in Ldlr-/- mice fed a Western diet. Pharmacological sGC stimulation further reduced atherosclerotic plaque formation and vascular inflammation. Conclusion: Loss of sGC in platelets contributes to atherosclerotic plaque formation via reduced release of the soluble factor angiopoietin-1 and, subsequently, enhanced leukocyte recruitment. Pharmacological sGC stimulation might represent a novel therapeutic strategy to prevent and treat CAD.

scholarly journals Palmitoylethanolamide Promotes a Proresolving Macrophage Phenotype and Attenuates Atherosclerotic Plaque Formation

2018 ◽  
Vol 38 (11) ◽  
pp. 2562-2575 ◽  
Author(s):  
Petteri Rinne ◽  
Raquel Guillamat-Prats ◽  
Martina Rami ◽  
Laura Bindila ◽  
Larisa Ring ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Plaque Formation ◽  
Macrophage Phenotype ◽  
Atherosclerotic Plaque Formation

scholarly journals The arterial microenvironment: the where and why of atherosclerosis

2016 ◽  
Vol 473 (10) ◽  
pp. 1281-1295 ◽  
Author(s):  
Arif Yurdagul ◽  
Alexandra C. Finney ◽  
Matthew D. Woolard ◽  
A. Wayne Orr
Keyword(s):  
Atherosclerotic Plaque ◽  
Inflammatory Cell ◽  
Plaque Formation ◽  
Cell Phenotype ◽  
Atherosclerotic Plaque Formation ◽  
Clinical Consequences

Changes in the local microenvironment regulate multiple aspects of vascular and inflammatory cell phenotype, determining the location, composition and clinical consequences of atherosclerotic plaque formation.

scholarly journals Pharmacological inhibition of protein tyrosine phosphatase 1B protects against atherosclerotic plaque formation in the LDLR−/− mouse model of atherosclerosis

2017 ◽  
Vol 131 (20) ◽  
pp. 2489-2501 ◽  
Author(s):  
Dawn Thompson ◽  
Nicola Morrice ◽  
Louise Grant ◽  
 Samantha Le Sommer ◽  
Emma K. Lees ◽  
...  
Keyword(s):  
Mouse Model ◽  
Atherosclerotic Plaque ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Plaque Formation ◽  
Negative Regulator ◽  
Protein Tyrosine Phosphatase 1B ◽  
Cvd Risk ◽  
Protein Tyrosine ◽  
Atherosclerotic Plaque Formation

Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with type 1 or type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance, due to impaired insulin receptor (IR) signalling. Here, we demonstrate that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR prevents and reverses atherosclerotic plaque formation in an LDLR−/− mouse model of atherosclerosis. Acute (single dose) or chronic PTP1B inhibitor (trodusquemine) treatment of LDLR−/− mice decreased weight gain and adiposity, improved glucose homeostasis and attenuated atherosclerotic plaque formation. This was accompanied by a reduction in both, circulating total cholesterol and triglycerides, a decrease in aortic monocyte chemoattractant protein-1 (MCP-1) expression levels and hyperphosphorylation of aortic Akt/PKB and AMPKα. Our findings are the first to demonstrate that PTP1B inhibitors could be used in prevention and reversal of atherosclerosis development and reduction in CVD risk.

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