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Platelets and their chemokines in atherosclerosis-clinical applications.

von Hundelshausen P, Schmitt MM - Front Physiol (2014)

Bottom Line: The chemokine CXCL4 has multiple atherogenic activities, e.g., altering the differentiation of T cells and macrophages by inhibiting neutrophil and monocyte apoptosis and by increasing the uptake of oxLDL and synergizing with CCL5.Atheroprotective and plaque stabilizing properties are attributed to CXCL12, which plays an important role in regenerative processes by attracting progenitor cells.Beyond the effects on the arterial inflammatory infiltrate, platelets affect cholesterol metabolism by binding, modifying and endocytosing LDL particles via their scavenger receptors and contribute to the formation of lipid laden macrophages.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University of Munich Munich, Germany ; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance Munich, Germany.

ABSTRACT
The concept of platelets as important players in the process of atherogenesis has become increasingly accepted due to accumulating experimental and clinical evidence. Despite the progress in understanding the molecular details of atherosclerosis, particularly by using animal models, the inflammatory and thrombotic roles of activated platelet s especially in the human system remain difficult to dissect, as often only the complications of atherosclerosis, i.e., stroke and myocardial infarction are definable but not the plaque burden. Platelet indices including platelet count and mean platelet volume (MPV) and soluble mediators released by activated platelets are associated with atherosclerosis. The chemokine CXCL4 has multiple atherogenic activities, e.g., altering the differentiation of T cells and macrophages by inhibiting neutrophil and monocyte apoptosis and by increasing the uptake of oxLDL and synergizing with CCL5. CCL5 is released and deposited on endothelium by activated platelets thereby triggering atherogenic monocyte recruitment, which can be attenuated by blocking the corresponding chemokine receptor CCR5. Atheroprotective and plaque stabilizing properties are attributed to CXCL12, which plays an important role in regenerative processes by attracting progenitor cells. Its release from luminal attached platelets accelerates endothelial healing after injury. Platelet surface molecules GPIIb/IIIa, GP1bα, P-selectin, JAM-A and the CD40/CD40L dyade are crucially involved in the interaction with endothelial cells, leukocytes and matrix molecules affecting atherogenesis. Beyond the effects on the arterial inflammatory infiltrate, platelets affect cholesterol metabolism by binding, modifying and endocytosing LDL particles via their scavenger receptors and contribute to the formation of lipid laden macrophages. Current medical therapies for the prevention of atherosclerotic therapies enable the elucidation of mechanisms linking platelets to inflammation and atherosclerosis.

No MeSH data available.


Related in: MedlinePlus

Effects of platelet-derived chemokines on inflammatory cells and atherogenesis. Chemokines are stored in α-granules and secreted upon activation. Most platelet-derived chemokines act on the one hand on inflammatory cell differentiation and apoptosis. On the other hand, they act on inflammatory cell adhesion to the endothelium with subsequent transendothelial migration. Thus, platelet-derived chemokines are crucial driving factors for atherogenesis. Further effects of platelet-derived chemokines are the retention of bone-marrow leukocytes and regulation of lipid transport.
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Figure 2: Effects of platelet-derived chemokines on inflammatory cells and atherogenesis. Chemokines are stored in α-granules and secreted upon activation. Most platelet-derived chemokines act on the one hand on inflammatory cell differentiation and apoptosis. On the other hand, they act on inflammatory cell adhesion to the endothelium with subsequent transendothelial migration. Thus, platelet-derived chemokines are crucial driving factors for atherogenesis. Further effects of platelet-derived chemokines are the retention of bone-marrow leukocytes and regulation of lipid transport.

Mentions: Research into fungi and cholesterol led to the development of statins (Endo et al., 1976), which inhibit the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) which is the first and key enzyme of cholesterol biosynthesis (Figure 2: statins: mechanisms of action), thereby preventing the generation of cholesterol precursors in the liver and reducing LDL-cholesterol, the pivotal cardiovascular risk factor. Cholesterol lowering statins are one of the most commonly used classes of atheroprotective drugs and so far exclusively proven to be beneficial in the primary prevention of myocardial infarction and stroke (Robinson, 2013). In clinical trials some of the protective properties of statins were not correlated with the reduction in cholesterol levels. At present it is unclear whether and to what extent LDL reduction or other modes of actions are responsible for the improved cardiovascular outcome in high risk patients. Anti-thrombotic, anti-inflammatory, endothelium protective, and plaque stabilizing properties are additional attributes of statins and outline the so-called pleiotropic, cholesterol independent, effects (Lefer et al., 2001; Liao and Laufs, 2005; Violi et al., 2013).


Platelets and their chemokines in atherosclerosis-clinical applications.

von Hundelshausen P, Schmitt MM - Front Physiol (2014)

Effects of platelet-derived chemokines on inflammatory cells and atherogenesis. Chemokines are stored in α-granules and secreted upon activation. Most platelet-derived chemokines act on the one hand on inflammatory cell differentiation and apoptosis. On the other hand, they act on inflammatory cell adhesion to the endothelium with subsequent transendothelial migration. Thus, platelet-derived chemokines are crucial driving factors for atherogenesis. Further effects of platelet-derived chemokines are the retention of bone-marrow leukocytes and regulation of lipid transport.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126210&req=5

Figure 2: Effects of platelet-derived chemokines on inflammatory cells and atherogenesis. Chemokines are stored in α-granules and secreted upon activation. Most platelet-derived chemokines act on the one hand on inflammatory cell differentiation and apoptosis. On the other hand, they act on inflammatory cell adhesion to the endothelium with subsequent transendothelial migration. Thus, platelet-derived chemokines are crucial driving factors for atherogenesis. Further effects of platelet-derived chemokines are the retention of bone-marrow leukocytes and regulation of lipid transport.
Mentions: Research into fungi and cholesterol led to the development of statins (Endo et al., 1976), which inhibit the 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMG-CoA reductase) which is the first and key enzyme of cholesterol biosynthesis (Figure 2: statins: mechanisms of action), thereby preventing the generation of cholesterol precursors in the liver and reducing LDL-cholesterol, the pivotal cardiovascular risk factor. Cholesterol lowering statins are one of the most commonly used classes of atheroprotective drugs and so far exclusively proven to be beneficial in the primary prevention of myocardial infarction and stroke (Robinson, 2013). In clinical trials some of the protective properties of statins were not correlated with the reduction in cholesterol levels. At present it is unclear whether and to what extent LDL reduction or other modes of actions are responsible for the improved cardiovascular outcome in high risk patients. Anti-thrombotic, anti-inflammatory, endothelium protective, and plaque stabilizing properties are additional attributes of statins and outline the so-called pleiotropic, cholesterol independent, effects (Lefer et al., 2001; Liao and Laufs, 2005; Violi et al., 2013).

Bottom Line: The chemokine CXCL4 has multiple atherogenic activities, e.g., altering the differentiation of T cells and macrophages by inhibiting neutrophil and monocyte apoptosis and by increasing the uptake of oxLDL and synergizing with CCL5.Atheroprotective and plaque stabilizing properties are attributed to CXCL12, which plays an important role in regenerative processes by attracting progenitor cells.Beyond the effects on the arterial inflammatory infiltrate, platelets affect cholesterol metabolism by binding, modifying and endocytosing LDL particles via their scavenger receptors and contribute to the formation of lipid laden macrophages.

View Article: PubMed Central - PubMed

Affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University of Munich Munich, Germany ; German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance Munich, Germany.

ABSTRACT
The concept of platelets as important players in the process of atherogenesis has become increasingly accepted due to accumulating experimental and clinical evidence. Despite the progress in understanding the molecular details of atherosclerosis, particularly by using animal models, the inflammatory and thrombotic roles of activated platelet s especially in the human system remain difficult to dissect, as often only the complications of atherosclerosis, i.e., stroke and myocardial infarction are definable but not the plaque burden. Platelet indices including platelet count and mean platelet volume (MPV) and soluble mediators released by activated platelets are associated with atherosclerosis. The chemokine CXCL4 has multiple atherogenic activities, e.g., altering the differentiation of T cells and macrophages by inhibiting neutrophil and monocyte apoptosis and by increasing the uptake of oxLDL and synergizing with CCL5. CCL5 is released and deposited on endothelium by activated platelets thereby triggering atherogenic monocyte recruitment, which can be attenuated by blocking the corresponding chemokine receptor CCR5. Atheroprotective and plaque stabilizing properties are attributed to CXCL12, which plays an important role in regenerative processes by attracting progenitor cells. Its release from luminal attached platelets accelerates endothelial healing after injury. Platelet surface molecules GPIIb/IIIa, GP1bα, P-selectin, JAM-A and the CD40/CD40L dyade are crucially involved in the interaction with endothelial cells, leukocytes and matrix molecules affecting atherogenesis. Beyond the effects on the arterial inflammatory infiltrate, platelets affect cholesterol metabolism by binding, modifying and endocytosing LDL particles via their scavenger receptors and contribute to the formation of lipid laden macrophages. Current medical therapies for the prevention of atherosclerotic therapies enable the elucidation of mechanisms linking platelets to inflammation and atherosclerosis.

No MeSH data available.


Related in: MedlinePlus