Elevated release of sCD40L from platelets of diabetic patients by thrombin, glucose and advanced glycation end products
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Published on: April 1, 2015
Nerea Varo1, Peter Libby, Rebecca Nuzzo
1Donald W Reynolds Cardiovascular Clinical Research Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Insights
Diabetic patients show increased CD40 ligand (CD40L) within platelets and greater release when stimulated. Glucose and advanced glycation end products (AGEs) may trigger this, explaining higher soluble CD40L (sCD40L) in diabetes.
Area of Science:
- Cardiovascular Biology
- Immunology
- Metabolic Disease Research
Background:
- The CD40/CD40L pathway is implicated in atherosclerosis.
- Elevated soluble CD40L (sCD40L) levels are observed in diabetic patients and predict cardiovascular events.
Purpose of the Study:
- To compare CD40/CD40L surface expression on platelets and T lymphocytes in diabetic and control subjects.
- To investigate if glucose and advanced glycation end products (AGEs) stimulate sCD40L release.
Main Methods:
- Compared surface CD40/CD40L expression on platelets and T lymphocytes.
- Assessed intracellular CD40L content in platelets.
- Measured sCD40L release from platelets stimulated by thrombin.
- Investigated the effect of glucose and AGEs on platelet sCD40L release and megakaryocyte CD40L expression.
Main Results:
- No differences in constitutive or inducible surface CD40/CD40L expression on platelets or T lymphocytes between groups.
- Diabetic patients had higher intracellular platelet CD40L.
- Thrombin-stimulated sCD40L release from platelets was significantly greater in diabetic patients.
- Glucose and AGEs induced sCD40L release and CD40L expression in vitro.
Conclusions:
- Diabetic patients exhibit increased intracellular CD40L in platelets and enhanced inducible sCD40L release.
- Glucose and AGEs are identified as potential triggers for elevated sCD40L in diabetic patients.
Abstract:
The pro-inflammatory CD40/CD40L dyad participates in atherogenesis. Plasma levels of the soluble ligand (sCD40L) predict cardiovascular events and are elevated in diabetic patients. This study compared CD40/CD40L surface expression on platelets and T lymphocytes of diabetic and control subjects, and tested whether glucose and advanced glycation end products (AGEs) stimulate sCD40L release. Constitutive and inducible surface expression of CD40/CD40L on platelets or T lymphocytes did not differ between diabetic patients (n = 9) and controls (n = 13). Platelets from diabetic patients contained higher intracellular CD40L than controls (p < 0.05) and thrombin stimulated greater platelet sCD40L release in diabetic patients (15.11 +/- 16.77 ng/ml) compared to controls (3.64 +/- 2.03 ng/ml; p < 0.05). Glucose and AGEs induced platelet sCD40L release and CD40L expression in mouse megakaryocytes. This study demonstrates elevated CD40L content and inducible release from platelets of diabetic patients, and identifies glucose and AGEs as potential triggers of expression and release accounting for the elevated sCD40L plasma levels in these patients.
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