Sulforaphane attenuates glycoprotein VI-mediated platelet mitochondrial dysfunction through up-regulating the cAMP/PKA signaling pathway <i>in vitro</i> and <i>in vivo</i>

Abstract

Platelet mitochondrial dysfunction is crucial for platelet activation, atherosclerosis and thrombosis. Sulforaphane (SFN) is a dietary isothiocyanate enriched in cruciferous vegetables and possesses multiple health benefits including cardiovascular protection. This study aims to investigate whether and how SFN modulates platelet mitochondrial dysfunction and hyperactivity <i>in vitro</i> and <i>in vivo</i>. Using a series of platelet functional assays in human platelets <i>in vitro</i>, we found that SFN at physiological concentrations attenuated oxidative stress-dependent platelet mitochondrial dysfunction (loss of mitochondrial membrane potential), apoptosis (cytochrome <i>c</i> release, caspase 3 activation and phosphatidylserine exposure) and activation induced by glycoprotein VI (GPVI) agonists (<i>e.g.</i>, collagen and convulxin). Moreover, 12-week supplementation of SFN-enriched broccoli sprout extract (BSE, 0.06% diet) in C57BL/6J mice also attenuated GPVI-induced platelet mitochondrial dysfunction, apoptosis and hyperreactivity <i>in vivo</i>. Mechanistically, these inhibitory effects of SFN treatment and BSE supplementation were mainly mediated by up-regulating the cAMP/PKA pathway though decreasing phosphodiesterase 3A (PDE3A) activity. Thus, through modulating the PDE3A/cAMP/PKA signaling pathway, and attenuating platelet mitochondrial dysfunction and hyperreactivity, SFN may be a potent cardioprotective agent.