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The PPAR-Platelet Connection: Modulators of Inflammation and Potential Cardiovascular Effects.

Spinelli SL, O'Brien JJ, Bancos S, Lehmann GM, Springer DL, Blumberg N, Francis CW, Taubman MB, Phipps RP - PPAR Res (2008)

Bottom Line: First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression.Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade.Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 608, Rochester,NY 14642,USA.

ABSTRACT
Historically, platelets were viewed as simple anucleate cells responsible for initiating thrombosis and maintaining hemostasis, but clearly they are also key mediators of inflammation and immune cell activation. An emerging body of evidence links platelet function and thrombosis to vascular inflammation. peroxisome proliferator-activated receptors (PPARs) play a major role in modulating inflammation and, interestingly, PPARs (PPARbeta/delta and PPARgamma) were recently identified in platelets. Additionally, PPAR agonists attenuate platelet activation; an important discovery for two reasons. First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression. Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade. Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.

No MeSH data available.


Related in: MedlinePlus

Platelets promote inflammation. CD40 expressing cells, such as endothelialcells or fibroblasts, can be activated by platelet-derived CD40L. CD40 signaling upregulates bioactivemediators in these cells; therefore, potentiating inflammation and increasingthe risk for CVD.
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Related In: Results  -  Collection


getmorefigures.php?uid=PMC2233896&req=5

fig1: Platelets promote inflammation. CD40 expressing cells, such as endothelialcells or fibroblasts, can be activated by platelet-derived CD40L. CD40 signaling upregulates bioactivemediators in these cells; therefore, potentiating inflammation and increasingthe risk for CVD.

Mentions: A surprising andimportant finding was that CD40L, a member of the tumor necrosis factor (TNF)receptor superfamily and a key mediator of both innate and adaptive immunity [4, 5, 35, 36], isreleased by activated platelets [31, 33, 35]. Shortly after platelets become activated, theyexpress CD40L on their surface which is subsequently enzymaticallycleaved releasing soluble bioactive CD40L into the bloodstream. This is highly significant for the followingtwo reasons. First, platelets contain approximately 95% of the CD40L found inhuman beings, and thus are a crucial link in the regulation of the CD40/CD40L pathway,as many cells express its receptor, CD40.These cells include fibroblasts, endothelial, epithelial, monocytes,neutrophils, B cells, and dendritic cells.CD40L is found in abnormallyhigh levels in the blood of patients with chronic inflammatory diseases such asdiabetes, atherosclerosis, as well as some recipients of platelet transfusions[33, 37–40]. Disruptionof CD40/CD40L pathway can blunt chronic inflammation, retardatherosclerosis, and transplant rejection [33, 35, 41]. Further, recent exciting researchdemonstrates that CD40L is crucial for stabilizing thrombi, for normal plateletresponses to sheer stress, and for platelet activation through the RGD domainof sCD40L which binds to platelet , a receptor critical for plateletactivation and aggregation [42, 43]. Collectively, these data strongly support the importance of CD40L as aprimary agonist for platelets and is considered a prototypical mediator withroles in both hemostasis and inflammation (Figure 1 summarizes CD40 activationby platelet CD40L). Therefore, the platelet is a crucial link inthe CD40/CD40L pathway and sCD40L release alone or in combination with otherproinflammatory mediators may increase the risk for cardiovascular effects promotingatherosclerosis, hypertension, and dyslipidemia to list a few.


The PPAR-Platelet Connection: Modulators of Inflammation and Potential Cardiovascular Effects.

Spinelli SL, O'Brien JJ, Bancos S, Lehmann GM, Springer DL, Blumberg N, Francis CW, Taubman MB, Phipps RP - PPAR Res (2008)

Platelets promote inflammation. CD40 expressing cells, such as endothelialcells or fibroblasts, can be activated by platelet-derived CD40L. CD40 signaling upregulates bioactivemediators in these cells; therefore, potentiating inflammation and increasingthe risk for CVD.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2233896&req=5

fig1: Platelets promote inflammation. CD40 expressing cells, such as endothelialcells or fibroblasts, can be activated by platelet-derived CD40L. CD40 signaling upregulates bioactivemediators in these cells; therefore, potentiating inflammation and increasingthe risk for CVD.
Mentions: A surprising andimportant finding was that CD40L, a member of the tumor necrosis factor (TNF)receptor superfamily and a key mediator of both innate and adaptive immunity [4, 5, 35, 36], isreleased by activated platelets [31, 33, 35]. Shortly after platelets become activated, theyexpress CD40L on their surface which is subsequently enzymaticallycleaved releasing soluble bioactive CD40L into the bloodstream. This is highly significant for the followingtwo reasons. First, platelets contain approximately 95% of the CD40L found inhuman beings, and thus are a crucial link in the regulation of the CD40/CD40L pathway,as many cells express its receptor, CD40.These cells include fibroblasts, endothelial, epithelial, monocytes,neutrophils, B cells, and dendritic cells.CD40L is found in abnormallyhigh levels in the blood of patients with chronic inflammatory diseases such asdiabetes, atherosclerosis, as well as some recipients of platelet transfusions[33, 37–40]. Disruptionof CD40/CD40L pathway can blunt chronic inflammation, retardatherosclerosis, and transplant rejection [33, 35, 41]. Further, recent exciting researchdemonstrates that CD40L is crucial for stabilizing thrombi, for normal plateletresponses to sheer stress, and for platelet activation through the RGD domainof sCD40L which binds to platelet , a receptor critical for plateletactivation and aggregation [42, 43]. Collectively, these data strongly support the importance of CD40L as aprimary agonist for platelets and is considered a prototypical mediator withroles in both hemostasis and inflammation (Figure 1 summarizes CD40 activationby platelet CD40L). Therefore, the platelet is a crucial link inthe CD40/CD40L pathway and sCD40L release alone or in combination with otherproinflammatory mediators may increase the risk for cardiovascular effects promotingatherosclerosis, hypertension, and dyslipidemia to list a few.

Bottom Line: First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression.Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade.Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Box 608, Rochester,NY 14642,USA.

ABSTRACT
Historically, platelets were viewed as simple anucleate cells responsible for initiating thrombosis and maintaining hemostasis, but clearly they are also key mediators of inflammation and immune cell activation. An emerging body of evidence links platelet function and thrombosis to vascular inflammation. peroxisome proliferator-activated receptors (PPARs) play a major role in modulating inflammation and, interestingly, PPARs (PPARbeta/delta and PPARgamma) were recently identified in platelets. Additionally, PPAR agonists attenuate platelet activation; an important discovery for two reasons. First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression. Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade. Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.

No MeSH data available.


Related in: MedlinePlus