Do the chemokines MDC and TARC contribute to obesity-related platelet hyperactivity and cardiovascular disease?

Obesity is a major risk factor for cardiovascular disease (CVD), with 65% of the UK adults overweight or obese. Obesity is associated with alterations in blood/plasma composition of hormones, peptides, lipids, and metabolites. Some of these factors are known to enhance platelet function (platelet priming) and may therefore contribute to antiplatelet drug resistance and risk of cardiovascular events. Previous studies suggested that the chemokines macrophage-derived chemokine (MDC or CCL22) and thymus and activation-regulated chemokine (TARC or CCL17), which both act at C-C Motif Chemokine Receptor 4 (CCR4), may be raised in obesity. These chemokines are important for the chemotaxis of leukocytes, but as platelets express CCR4, they may also enhance platelet function. In this study, we therefore aimed (1) to determine whether MDC and TARC can potentiate platelet function ex vivo, and (2) to explore how body mass index (BMI) is associated with blood levels of MDC/TARC and whether these chemokines contribute to CVD. Preincubating washed platelets with MDC or TARC potentiated platelet aggregation and integrin αIIbβ3 activation induced by the agonist PAR1-AP, without altering PAR1-AP induced alpha granule secretion. Regressing levels of MDC and TARC on BMI revealed a strong positive association between BMI and levels of MDC, but no association with TARC. A two-sample Mendelian randomization study suggested increased levels of MDC contributes to cardiovascular events such as deep vein thrombosis and pulmonary embolism. In conclusion, both MDC and TARC have the ability to prime platelets, but only MDC is associated with BMI and contributes to cardiovascular disease.