Abstract
Platelet multidrug resistance protein 4 (MRP4) plays a modulating role on platelet activation. Platelet function and thrombus formation are impaired in MRP4 knockout mice models, and, among aspirin-treated patients, high on-aspirin residual platelet reactivity (HARPR) positively correlates with MRP4 levels. To better understand the effects of MRP4 on platelet function, the aim of this investigation was to assess the impact of cilostazol-induced inhibition of MRP4-mediated transport and assess aspirin-induced antiplatelet effects and rates of HARPR in human subjects.Cilostazol-dependent inhibition of MRP4-mediated transport was assessed with the release of the fluorescent adduct bimane-glutathione and aspirin entrapment. Effect of Cilostazol on cAMP inhibition was evaluated by vasodilator-stimulated phosphoprotein (VASP). Platelet function was studied by collagen and TRAP-6-induced platelet aggregation and secretion.Cilostazol reduced the release of bimane-glutathione and enhanced aspirin entrapment demonstrating an inhibitory effect on MRP4 in platelets. VASP phosphorylation was absent until 10 seconds after addition of cilostazol, and becomes evident after 30 seconds. An inhibitory effect on platelet aggregation and secretion was found in activated platelets, with threshold concentration of agonists, 10 seconds after addition of cilostazol, supporting a role of MRP4 on platelet function that is cAMP independent. Cilostazol effects were also shown in aspirin-treated platelets. A reduction of platelet aggregation and secretion were observed in aspirin-treated patients with HARPR.This study supports the role of MRP4 on modulating platelet function which occurs through cAMP-independent mechanisms. Moreover, inhibition of MRP4 induced by cilostazol enhances aspirin-induced antiplatelet effects and reduces HARPR.
Highlights
New-onset atrial fibrillation (AF) is common after cardiac surgery, with an incidence of 30 to 50%.1–3 Patients developing de novo AF after cardiac surgery (AFACS) have a higher risk of developing persistent/long-term AF in the community.[4]
Even though little detail is known about the precise molecular mechanisms underlying the onset and perpetuation of AFACS, recent evidence points to proarrhythmic mechanisms acting on a background of structural remodeling
Systemic inflammation and oxidative stress have been shown to be associated with increased incidence of AFACS.[10,11]
Summary
Accurate risk quantification for AFACS has been one of the holy grails of research in cardiothoracic perioperative medicine. The quest for risk factors and models has been relatively unrewarding so far, despite a lot having been published. Even though little detail is known about the precise molecular mechanisms underlying the onset and perpetuation of AFACS, recent evidence points to proarrhythmic mechanisms acting on a background of structural remodeling. A remodeled atrial tissue, with structural changes, increased wall strain, and increased chamber dimensions, is much more sensitive to the effects of proinflammatory cytokines, reactive oxygen species, and increased adrenergic drive.[10] Surgical trauma and ischemia and reperfusion from the use of cardioplegia and cardiopulmonary bypass lead to oxidative stress and production of proinflammatory molecules, resulting in endothelial activation. Systemic inflammation and oxidative stress have been shown to be associated with increased incidence of AFACS.[10,11] Details of the conceptual model underpinning this are beyond the scope of this editorial note. It is worth pointing out that structural remodeling of the atrial tissue, together with connexin and ion-channel remodeling, is among the possible mechanisms proposed.[12]
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