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SummaryLow Density Lipoprotein (LDL) is known to sensitize platelets for physiological agonists. To clarify the basis of this sensitization, we investigated the involvement of p38MAP Kinase (p38MAPK). As dual phosphorylation on Thr180 and Tyr182 of p38MAPK is the trigger for activation of the kinase, p38MAPK-activity was measured with an antibody that recognizes the dual-phosphorylated sequence. LDL induced a rapid and dose dependent activation of p38MAPK. The activation was not inhibited by a wide variety of inhibitors of platelet signalling, including TxA2-formation, Phospholipase C-activation, Ca2+-mobilization and ERK 1/2-activation. Only a slight reduction in p38MAPK-activation was observed when protein kinase C was inhibited. Activation of p38MAPK was strongly inhibited by a rise in cAMP. Thus, p38MAPK-activation was upstream of most signalling pathways and close to the LDL-receptor. A number of platelet receptors was screened with the use of antibodies. Integrins αIIbβ3 and α2β1, as well as the FcγRII-receptor, CD36 (platelet glycoprotein IV), CD68 (gp110) and Low Density Lipoprotein-receptor related protein (LRP) were not implicated in LDL-induced p38MAPK-activation. Inhibition of LDL binding by modification of apo B100 lysines reduced p38MAPK-activation by 80 %. Activation of p38MAPK resulted in an increase in release of arachidonic acid, the precursor for thromboxane A2 synthesis. In conclusion, activation of p38MAPK might be the first step in platelet sensitization by LDL, leading to formation of arachidonate metabolites and increased aggregation and secretion responses to physiological agonists.

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Abstract-LDL is known to increase the sensitivity of human platelets for agonists and to induce aggregation and secretion independently at high concentrations, but its mechanism of action is largely obscure. To clarify how LDL increases platelet sensitivity, cells were incubated in lipoprotein-poor plasma and treated with collagen at a concentration that induced Ϸ20% secretion of 14 C-serotonin. Preincubation with LDL (30 minutes at 37°C) enhanced secretion in a dose-dependent manner to 60Ϯ14% at a concentration of 2 g LDL protein/L. Similar stimulation by LDL was seen when secretion was induced by the thrombin receptor-activating peptide. This enhancement was strongly reduced (1)

Oral magnesium (Mg) supplementation can improve insulin sensitivity and secretion in patients with Type 2 diabetes mellitus (DM). We studied the effect of Mg supplementation on glycaemic control, blood pressure, and plasma lipids in insulin-requiring patients with Type 2 DM. Fifty moderately controlled patients were randomized to 15 mmol Mg or placebo daily for 3 months. Plasma Mg, glucose, HbA1c, lipids, erythrocyte Mg, Mg and glucose concentrations in 24-h urine, and systolic and diastolic pressure were measured before and after 3 months treatment. Plasma Mg concentration was higher after supplementation than after placebo (0.82 +/- 0.07 vs 0.78 +/- 0.08 mmol l(-1), p < 0.05), as was Mg excretion (5.5 +/- 1.9 vs 3.7 +/- 1.4 mmol 24 h(-1), p = 0.004) but erythrocyte Mg concentrations were similar. No significant differences were found in glycaemic control (glucose: 10.7 +/- 3.8 vs 11.6 +/- 6.2 mmol l(-1), p = 0.8; HbA1c: 8.9 +/- 1.6 vs 9.1 +/- 1.2%, p = 0.8), lipids or blood pressure. On-treatment analysis (34 patients: 18 on Mg, 16 on placebo) yielded similar results. An increase in plasma Mg concentration irrespective of medication was associated with a tendency to a decrease in diastolic pressure (increased plasma Mg vs no increase: -4.0 +/- 10.1 vs +2.5 +/- 12.0 mmHg, p = 0.059). Three months' oral Mg supplementation of insulin-requiring patients with Type 2 DM increased plasma Mg concentration and urinary Mg excretion but had no effect on glycaemic control or plasma lipid concentrations.