The role of PGE2 in human atherosclerotic plaque on platelet EP3 and EP4 receptor activation and platelet function in whole blood

2011 ◽  
Vol 32 (2) ◽  
pp. 158-166 ◽  
Author(s):  
Lisa J. Schober ◽  
Anna L. Khandoga ◽  
Suman Dwivedi ◽  
Sandra M. Penz ◽  
Takayuki Maruyama ◽  
...  
Keyword(s):  
Platelet Function ◽  
Atherosclerotic Plaque ◽  
Whole Blood ◽  
Receptor Activation ◽  
Human Atherosclerotic Plaque ◽  
Ep4 Receptor

The role of neovascularization in the formation of an unstable human atherosclerotic plaque

2021 ◽  
Vol 83 (3) ◽  
pp. 5
Author(s):  
P.V. Pigarevsky ◽  
R.A. Vorozhbit ◽  
V.A. Snegova ◽  
V.A. Guseva ◽  
S.V. Maltseva ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Human Atherosclerotic Plaque

scholarly journals Evidence Supporting a Key Role of Lp-PLA2-Generated Lysophosphatidylcholine in Human Atherosclerotic Plaque Inflammation

2012 ◽  
Vol 32 (6) ◽  
pp. 1505-1512 ◽  
Author(s):  
Isabel Gonçalves ◽  
Andreas Edsfeldt ◽  
Na Young Ko ◽  
Helena Grufman ◽  
Katarina Berg ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Human Atherosclerotic Plaque ◽  
Plaque Inflammation

scholarly journals Myeloid Mineralocorticoid Receptor Transcriptionally Regulates P-Selectin Glycoprotein Ligand-1 and Promotes Monocyte Trafficking and Atherosclerosis

2021 ◽  
Author(s):  
Joshua J. Man ◽  
Qing Lu ◽  
M. Elizabeth Moss ◽  
Brigett Carvajal ◽  
Wendy Baur ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Mineralocorticoid Receptor ◽  
Myeloid Cells ◽  
Receptor Activation ◽  
Leukocyte Trafficking ◽  
Response Element ◽  
Increased Risk ◽  
Plaque Inflammation ◽  
The Impact

Objective: MR (mineralocorticoid receptor) activation associates with increased risk of cardiovascular ischemia while MR inhibition reduces cardiovascular-related mortality and plaque inflammation in mouse atherosclerosis. MR in myeloid cells (My-MR) promotes inflammatory cell infiltration into injured tissues and atherosclerotic plaque inflammation by unclear mechanisms. Here, we examined the role of My-MR in leukocyte trafficking and the impact of sex. Approach and Results: We confirm in vivo that My-MR deletion (My-MR-KO) in ApoE-KO mice decreased plaque size. Flow cytometry revealed fewer plaque macrophages with My-MR-KO. By intravital microscopy, My-MR-KO significantly attenuated monocyte slow-rolling and adhesion to mesenteric vessels and decreased peritoneal infiltration of myeloid cells in response to inflammatory stimuli in male but not female mice. My-MR-KO mice had significantly less PSGL1 (P-selectin glycoprotein ligand 1) mRNA in peritoneal macrophages and surface PSGL1 protein on circulating monocytes in males. In vitro, MR activation with aldosterone significantly increased PSGL1 mRNA only in monocytes from MR-intact males. Similarly, aldosterone induced, and MR antagonist spironolactone inhibited, PSGL1 expression in human U937 monocytes. Mechanistically, aldosterone stimulated MR binding to a predicted MR response element in intron-1 of the PSGL1 gene by ChIP-qPCR. Reporter assays demonstrated that this PSGL1 MR response element is necessary and sufficient for aldosterone-activated, MR-dependent transcriptional activity. Conclusions: These data identify PSGL1 as a My-MR target gene that drives leukocyte trafficking to enhance atherosclerotic plaque inflammation. These novel and sexually dimorphic findings provide insight into increased ischemia risk with MR activation, cardiovascular protection in women, and the role of MR in atherosclerosis and tissue inflammation.

The pro-inflammatory role of sphingolipids and glycosphingolipids in the human atherosclerotic plaque

2015 ◽  
Vol 241 (1) ◽  
pp. e30
Author(s):  
A. Edsfeldt ◽  
P. Dunér ◽  
M. Ståhlman ◽  
I.G. Mollet ◽  
G. Asciutto ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Human Atherosclerotic Plaque

The Transient Receptor-Potential Channel 6 Plays a Critical Role In Platelet Function

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3201-3201
Author(s):  
John P Murad ◽  
Harold J Ting ◽  
Fadi T. Khasawneh
Keyword(s):  
Platelet Activation ◽  
Platelet Function ◽  
Calcium Homeostasis ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Receptor Activation ◽  
Calcium Entry ◽  
Transient Receptor

Abstract Abstract 3201 In spite of the fact that changes in the intracellular levels of calcium (e.g., calcium entry (CE)) is a central step in platelet activation, the underlying mechanism of this CE is still ill defined. Previous studies have demonstrated that of the transient receptor potential channel (TRPC) family, TRPC1 and, to a higher extent, TRPC6 are expressed in blood platelets, whereas TRPC4 is found in megakaryocytes (at the mRNA level). Furthermore, recent studies have shown that TRPC1 deficient platelets exhibited no defects in platelet function, and unaltered calcium homeostasis. Based on these considerations, we hypothesized that TRPC6 plays an essential role in receptor-operated calcium entry and platelet function. Our preliminary studies reveal that platelets deficient in TRPC6 exhibited a defect in platelet aggregation mediated by the thromboxane receptor (TPR), at least, at low agonist levels (i.e., low levels of receptor activation). Moreover, TRPC6 deficient mice also exhibited a significantly prolonged bleeding time, and were protected against thrombosis development, using a FeCl3 carotid-artery injury model. Together, these findings are consistent with the role of TPRs in hemostasis and the genesis of thrombosis. In future studies, we will investigate the role of TRPC6 in: 1. calcium homeostasis; 2. separate platelet functional responses such as dense granule secretion and shape change; and 3. in platelet activation via separate platelet G-protein coupled receptors such as PAR4 and P2Y1. These studies may define a new therapeutic target for managing multiple thrombosis-based disorders. Disclosures: No relevant conflicts of interest to declare.

Phosphoinositide 3-kinases and the regulation of platelet function

2004 ◽  
Vol 32 (2) ◽  
pp. 387-392 ◽  
Author(s):  
S.P. Jackson ◽  
C.L. Yap ◽  
K.E. Anderson
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Critical Role ◽  
Receptor Activation ◽  
Clear Understanding ◽  
Integrin Αiibβ3 ◽  
Adhesion Receptor ◽  
Input Signals

A clear understanding of the role of PI (phosphoinositide) 3-kinases in supporting the haemostatic function of platelets has been slow to evolve. In fact, insight into the roles of individual PI 3-kinase isoforms in platelet function remains rudimentary. However, based on in vitro studies using wortmannin and LY294002, there is evidence for an important role for PI 3-kinases in regulating a broad range of functional platelet responses, including primary platelet adhesion, cytoskeletal remodelling and platelet aggregation. One of the critical platelet responses involves affinity regulation of the major platelet integrin αIIbβ3, the primary receptor mediating platelet aggregation and thrombus growth. The input signals regulating integrin αIIbβ3 can be divided into three main groups: (1) Gq-coupled receptors linked to the activation of PLCβ (phospholipase Cβ); (2) Gi-coupled receptors linked to the regulation of adenylate cyclase and Rap1b; and (3) adhesion receptor signalling involving Src kinase-dependent activation of PLCγ isoforms. PI 3-kinases have not been demonstrated to play a critical role in Gq-dependent platelet activation; however, one or more PI 3-kinase isoforms appears to be important for Gi-dependent activation of Rap1b and adhesion receptor activation of PLCγ isoforms. Thus distinct co-operative PI 3-kinase signalling mechanisms appear to play an important role in regulating the adhesive function of integrin αIIbβ3.

Effect of Dipyridamole on Spontaneous Platelet Aggregation in Whole Blood Decreases with the Time After Venepuncture: Evidence for the Role of ADP

1987 ◽  
Vol 58 (02) ◽  
pp. 744-748 ◽  
Author(s):  
A R Saniabadi ◽  
G D O Lowe ◽  
J C Barbenel ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Correlation Coefficient ◽  
Whole Blood ◽  
Blood Platelet ◽  
Inhibitory Effect ◽  
Time Interval ◽  
Adp Receptor ◽  
Spontaneous Platelet Aggregation

SummarySpontaneous platelet aggregation (SPA) was studied in human whole blood at 3, 5, 10, 20, 30, 40 and 60 minutes after venepuncture. Using a whole blood platelet counter, SPA was quantified by measuring the fall in single platelet count upon rollermixing aliquots of citrated blood at 37° C. The extent of SPA increased with the time after venepuncture, with a correlation coefficient of 0.819. The inhibitory effect of dipyridamole (Dipy) on SPA was studied: (a) 10 μM at each time interval; (b) 0.5-100 μM at 3 and 30 minutes and (c) 15 μM in combination with 100 μM adenosine, 8 μM 2-chloroadenosine (2ClAd, an ADP receptor blocker) and 50 μM aspirin. There was a rapid decrease in the inhibitory effect of Dipy with the time after venepuncture; the correlation coefficient was -0.533. At all the concentrations studied, Dipy was more effective at 3 minutes than at 30 minutes after venepuncture. A combination of Dipy with adenosine, 2ClAd or aspirin was a more effective inhibitor of SPA than either drug alone. However, when 15 μM Dipy and 10 μM Ad were added together, the inhibitory effect of Dipy was not increased significantly, suggesting that Dipy inhibits platelet aggregation independent of Ad. The increase in SPA with the time after venepuncture was abolished when blood was taken directly into the anticoagulant containing 5 μM 2ClAd. It is suggested that ADP released from the red blood cells is responsible for the increased platelet aggregability with the time after venepuncture and makes a serious contribution to the artifacts of in vitro platelet function studies.

Haemostatic Platelet Plug Formation in the Isolated Rabbit Mesenteric Preparation - An Analysis of Red Blood Cell Participation

1980 ◽  
Vol 44 (01) ◽  
pp. 006-008 ◽  
Author(s):  
D Bergqvist ◽  
K-E Arfors
Keyword(s):  
Whole Blood ◽  
Platelet Rich Plasma ◽  
Adenosine Diphosphate ◽  
In Vitro Test ◽  
Pharmacological Agents ◽  
Vitro Test ◽  
Releasing Effect ◽  
Plug Formation

SummaryIn a model using an isolated rabbit mesenteric preparation microvessels were transected and the time until haemostatic plugs formed was registered. Perfusion of platelet rich plasma gave no haemostasis whereas whole blood did. Addition of chlorpromazine or adenosine to the whole blood significantly prolonged the time for haemostasis, and addition of ADP to the platelet rich plasma significantly shortened it. It is concluded that red cells are necessary for a normal haemostasis in this model, probably by a combination of a haemodynamic and ADP releasing effect.The fundamental role of platelets in haemostatic plug formation is unquestionable but there are still problems concerning the stimulus for this process to start. Three platelet aggregating substances have been discussed – thrombin, adenosine diphosphate (ADP) and collagen. Evidence speaking in favour of thrombin is, however, very minimal, and the discussion has to be focused on collagen and ADP. In an in vitro system using polyethylene tubings we have shown that "haemostasis" can be obtained without the presence of collagen but against these results can be argued that it is only another in vitro test for platelet aggregation (1).To be able to induce haemostasis in this model, however, the presence of red blood cells is necessary. To further study this problem we have developed a model where haemostatic plug formation can be studied in the isolated rabbit mesentery and we have briefly reported on this (2).Thus, it is possible to perfuse the vessels with whole blood as well as with platelet rich plasma (PRP) and different pharmacological agents of importance.

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