Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Patel, Madhukar S.; Miranda-Nieves, David; Chen, Jiaxuan; Haller, Carolyn A.; Chaikof, Elliot L.

doi:10.1016/j.trsl.2016.11.007

Cited by 39 publications

(31 citation statements)

References 188 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This may highlight that the serological cellular adhesion molecules may be modifiable with 16 weeks of exenatide treatment whereas RH-PAT may require more time to show a significant change, and clarification of these functional findings with longer studies involving serial measurement of the serum endothelial markers are required. The correlation of decreased ICAM-1 with triglycerides and p-selectin with hip circumference is in accord with their relationship with metabolic syndrome and their reduction that reflected the weight loss (37, 38).…”

Section: Discussionsupporting

confidence: 57%

The Effect of Exenatide on Cardiovascular Risk Markers in Women With Polycystic Ovary Syndrome

et al. 2019

View full text Add to dashboard Cite

Background: Polycystic ovary syndrome (PCOS) is associated with an adverse cardiovascular risk profile including a prothrombotic state. Exenatide has been shown to be effective at improving insulin sensitivity and weight loss in PCOS; therefore this study was undertaken to assess its effects on weight, endothelial function, inflammatory markers, and fibrin structure/function in overweight/obese women with PCOS. Methods: Thirty overweight/obese anovulatory women with all 3 Rotterdam criteria received exenatide 5 mcg bd for 4 weeks then 10 mcg bd for 12 weeks. The primary outcome was change in weight; secondary outcomes were changes in endothelial function [Reactive Hyperemia-Peripheral Arterial Tonometry (RH-PAT)], serum endothelial markers (ICAM-1, VCAM-1, E-selectin, and P-selectin), change in inflammation (hsCRP), and alteration in clot structure and function [maximum absorbance (MA), and time from full clot formation to 50% lysis (LT)]. Results: Twenty patients completed the study. Exenatide reduced weight 111.8 ± 4.8 to 108.6 ± 4.6 kg p = 0.003. Serum endothelial markers changed with a reduction in ICAM-1 (247.2 ± 12.9 to 231.3 ± 11.5 ng/ml p = 0.02), p-selectin (101.1 ± 8.2 to 87.4 ± 6.6 ng/ml p = 0.01), and e-selectin (38.5 ± 3.3 to 33.6 ± 2.6 ng/ml p = 0.03), without an overt change in endothelial function. Inflammation improved (CRP; 8.5 ± 1.4 to 5.6 ± 0.8 mmol/L p = 0.001), there was a reduction in clot function (LT; 2,987 ± 494 to 1,926 ± 321 s p = 0.02) but not clot structure. Conclusion: Exenatide caused a 3% reduction in weight, improved serum markers of endothelial function, inflammation, and clot function reflecting an improvement in cardiovascular risk indices in these women with PCOS. This suggests exenatide could be an effective treatment for obese women with PCOS. Clinical Trial Registration: ISRCTN81902209.

show abstract

Section: Discussionsupporting

confidence: 57%

The Effect of Exenatide on Cardiovascular Risk Markers in Women With Polycystic Ovary Syndrome

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The circulating levels of soluble form of P-selectin mirror platelet activation. Stored in the alpha-granules of platelets, in a setting of inflammation P-selectin translocates to the plasma membrane where it can interact with ligands [84] leading to leukocyte-platelet aggregates that promote adhesion and infiltration of inflammatory cells [85][86][87][88]. sP-selectin has been associated with adiposity and both clinical and subclinical atherosclerosis [89] and has been shown to predict atherosclerosis independently of BMI and other CVD risk factors.…”

Section: Soluble P-selectinmentioning

confidence: 99%

Influence of Cardiometabolic Risk Factors on Platelet Function

Barale

Russo

2020

IJMS

View full text Add to dashboard Cite

Platelets are key players in the thrombotic processes. The alterations of platelet function due to the occurrence of metabolic disorders contribute to an increased trend to thrombus formation and arterial occlusion, thus playing a major role in the increased risk of atherothrombotic events in patients with cardiometabolic risk factors. Several lines of evidence strongly correlate metabolic disorders such as obesity, a classical condition of insulin resistance, dyslipidemia, and impaired glucose homeostasis with cardiovascular diseases. The presence of these clinical features together with hypertension and disturbed microhemorrheology are responsible for the prothrombotic tendency due, at least partially, to platelet hyperaggregability and hyperactivation. A number of clinical platelet markers are elevated in obese and type 2 diabetes (T2DM) patients, including the mean platelet volume, circulating levels of platelet microparticles, oxidation products, platelet-derived soluble P-selectin and CD40L, thus contributing to an intersection between obesity, inflammation, and thrombosis. In subjects with insulin resistance and T2DM some defects depend on a reduced sensitivity to mediators-such as nitric oxide and prostacyclin-playing a physiological role in the control of platelet aggregability. Furthermore, other alterations occur only in relation to hyperglycemia. In this review, the main cardiometabolic risk factors, all components of metabolic syndrome involved in the prothrombotic tendency, will be taken into account considering some of the mechanisms involved in the alterations of platelet function resulting in platelet hyperactivation.

show abstract

“…PSGL-1 activates intracellular protein kinases, such as mitogen-activated protein kinase, which controls the expression of various pro-inflammatory cytokines 40 . Targeting P-selectin and PSGL1 interactions holds significant potential for the treatment of inflammatory disorders 41–43 . TLR4 receptor is abundantly present on the surface of DCs and is involved in the formation of foam cells and promotion of atherosclerotic plaque formation 12,44 .…”

Section: Discussionmentioning

confidence: 99%

The P-selectin and PSGL-1 axis accelerates atherosclerosis via activation of dendritic cells by the TLR4 signaling pathway

Zhong

Zhu

et al. 2019

Cell Death Dis

View full text Add to dashboard Cite

P-selectin and dendritic cells (DCs) are associated with atherosclerosis. However, their interactions in this setting are undefined. Herein, we investigated the role of P-selectin and its receptor P-selectin glycoprotein ligand (PSGL)-1 on atherosclerosis via activation of DCs. In the current study, a total of 34 patients with ST elevation myocardial infarction (STEMI) and 34 healthy control subjects were enrolled. Serum concentration of P-selectin was higher and the myeloid DC/plasmacytoid DC (mDC/pDC) ratio was lower in STEMI patients than in normal individuals. Interestingly, in STEMI patients, P-selectin was decreased and the mDC/pDC ratio was increased at 5–7 days after successful percutaneous coronary intervention, as compared with values on admission. Serum P-selectin was inversely correlated with the mDC/pDC ratio. Moreover, ApoE −/− P −/− and ApoE −/− PSGL-1 −/− mice developed small atherosclerotic plaques after feeding of a western diet for 12 weeks and DC infiltration was significantly reduced. P-selectin stimulation markedly induced phenotypic maturation, enhanced secretion of inflammatory cytokines, communication with T cells, and the adhesion and migration of DCs. In vivo, DC maturation was significantly attenuated in P-selectin and PSGL1 knockout mice under hypercholesterolemic and inflammatory conditions. These effects were associated with the activation of myeloid differentiation primary response 88 (MYD88)-dependent and MyD88-independent Toll-like receptor 4 (TLR4) signaling pathways. Taken together, binding of P-selectin to PSGL-1 on DCs contributes to atherosclerosis progression via DC activation via the TLR4 signaling pathway.

show abstract

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

Cited by 39 publications

References 188 publications

The Effect of Exenatide on Cardiovascular Risk Markers in Women With Polycystic Ovary Syndrome

The Effect of Exenatide on Cardiovascular Risk Markers in Women With Polycystic Ovary Syndrome

Influence of Cardiometabolic Risk Factors on Platelet Function

The P-selectin and PSGL-1 axis accelerates atherosclerosis via activation of dendritic cells by the TLR4 signaling pathway

Contact Info

Product

Resources

About