Platelet derived serotonin drives the activation of rat cardiac fibroblasts by 5-HT2A receptors

Platelet activation occurs in different acute and chronic heart diseases including myocardial infarction, obstructive hypertrophic cardiomyopathy and valve stenosis. Recent studies suggested that some factors secreted by activated platelets may participate in cardiac remodeling. In the present study, we investigated whether platelets and platelet-released serotonin (5-HT) are directly involved in the functional regulation of cardiac fibroblasts. Treatment of neonatal rat cardiac fibroblasts with platelet lysate, 5-HT and the 5-HT2A receptor agonist DOI increased the expression of α-SMA protein, a marker of fibroblast differentiation into myofibroblasts. Platelet lysate, 5-HT and DOI also induced a time-dependent stimulation of cardiac fibroblast migration that was inhibited by the 5-HT2A receptor antagonist ketanserin. Finally, incubation of cardiac fibroblasts with platelet lysate or 5-HT enhanced secretion of TGF-β1 and expression of MMP-3 and MMP-13. As observed for fibroblast migration, these effects were prevented by ketanserin. These results demonstrated for the first time that factors released from platelet directly regulate cardiac fibroblasts by enhancing secretion of TGF-β1 and MMPs and promoting their migration and differentiation. 5-HT released by platelets appears to be a major contributor of platelet effects which are mediated through 5-HT2A receptors.