Antioxidant and antiplatelet effects of atorvastatin by Nox2 inhibition

Abstract

In recent years, it became evident that reactive oxygen species (ROS) are implicated in the thrombotic process. Statins are lipid-lowering agents able to lower serum cholesterol levels and retard atherosclerotic complications and their clinical sequelae. There is evidence that, among statins, atorvastatin may exert antiplatelet effects by interfering with redox signaling. Recent studies demonstrated that atorvastatin possesses antiplatelet activity via inhibition of platelet formation of NADPH oxidase-derived ROS. This effect results in down-regulation of isoprostanes, which are pro-aggregating molecules, and up-regulation of nitric oxide, which is a platelet inhibitor; such changes occurred immediately after atorvastatin administration and were independent from lipid-lowering property. Experimental and clinical studies documented that statins possess antithrombotic effects, which may account for the reduction of thrombotic-related vascular outcomes. This has been evidenced in different cardiovascular clinical settings such as percutaneous coronary intervention (PCI), myocardial infarction (MI), and venous thrombosis. Future studies should be addressed to analyze if the antiplatelet effect of atorvastatin may preferentially occur at high dosage. Interestingly, the antiplatelet effects of statins could be useful in clinical settings where the clinical efficacy of aspirin and other antiplatelet drugs is still uncertain.

Introduction

Reactive oxygen species (ROS) are chemically unstable molecules, which rapidly react with other molecules giving formation of oxidized products such as oxidized low-density lipoprotein (LDL), peroxy-nitrite, or protein adducts (Sugamura and Keaney, 2011). At physiologic concentration, ROS serve as second messengers, behaving as intracellular signals for cell activation (Sugamura and Keaney, 2011). This process is particularly evident in platelets, where ROS are directly implicated in cell activation. Upon activation by common agonists, platelets produce several types of ROS like superoxide anion or hydrogen peroxide, which contribute to propagation of platelet aggregation (Violi and Pignatelli, 2012). The knowledge of mechanisms underlying up-regulation of ROS could be useful to work out an effective therapeutic approach to modulate oxidative stress in the setting of athero-thrombosis. Basic, experimental and clinical studies provided definite evidence on the key role played by platelets in the process of athero-thrombosis. Therefore, interventional trials with aspirin (a platelet COX-1 inhibitor) (Vane, 1971), thienopyridines such as ticlopidine or clopidogrel (a platelet P2Y₁₂ receptor inhibitor) (Cattaneo, 2004), or the combination of the two drugs, i.e., aspirin plus clopidogrel, reduced clinical outcomes in patients with acute coronary syndromes (ACS) (Yusuf et al., 2001). Meta-analysis of trials with antiplatelet drugs in patients with stable atherosclerosis, such as those with stable angina, peripheral arterial disease, or cerebro-vascular diseases, confirmed the clinical efficacy of this drugs' category (Antithrombotic Trialists, 2002).

Despite the encouraging results obtained from interventional trials, the real world of athero-thrombosis is still burdened by a high rate of morbidity and mortality. There are several issues that may potentially account for the lack of effect of some antithrombotic treatments and cardiovascular relapses. For example, poor adherence to prescribed therapy may play a relevant role in this context, as shown by the higher rate of adverse events and hospital readmission in patients who do not completely adhere to aspirin treatment (Cotter et al., 2004). Concomitant multiple anti-atherosclerotic treatments are an important cause of poor aspirin compliance and should be taken into account in monitoring patients' adherence to antiplatelet treatment (Pignatelli et al., 2008). Insufficient antiplatelet effect of the drugs currently available for clinical use may be another relevant explanation for vascular relapses (Violi and Pignatelli, 2006). Recently, prasugrel, a new P2Y₁₂ receptor antagonist, reduced vascular complications in patients with ACS (Montalescot et al., 2009) when compared to clopidogrel.

Another explanation for this “apparent” partial protective action may be found in the inability of most drugs in modulating platelet ROS formation. In fact, experimental and clinical studies demonstrated that aspirin minimally affects platelet production of ROS (Basili et al., 2011, Leo et al., 1997, Pignatelli et al., 1998), and it is still unclear if thienopyridines have some influence on the platelet production of ROS (Evangelista et al., 2005). A crucial issue is, however, to establish if inhibition of ROS formation has implications for platelet activation and for clinical progression of atherosclerotic diseases. Recent studies on this topic suggest that modulating the generation or blunting ROS activity is translated to inhibition of platelet aggregation (Pignatelli et al., 2011). In this context, recent data showed a role for statins in impairing platelet ROS formation; this effect contributes to the inhibition of platelet cellular intra-signaling that ultimately leads to platelet activation (Pignatelli et al., 2012a, Pignatelli et al., 2012b). This effect of statins may be of clinical relevance as it can explain some of the beneficial properties that cannot be solely related to the statins' lipid-lowering efficacy. This review deals with the relationship between statins and platelet activation, focusing in particular on the antioxidant effect of statins through the impairing of platelet ROS formation. Furthermore, we will analyze the potential clinical implications of this statin property in the setting of athero-thrombosis.