Association between High On-Aspirin Platelet Reactivity and Reduced Superoxide Dismutase Activity in Patients Affected by Type 2 Diabetes Mellitus or Primary Hypercholesterolemia.

Cristina Barale,Chiara Frascaroli,Angelo Guerrasio,Alessandro Morotti,Isabella Russo,Franco Cavalot,Katia Bonomo

doi:10.3390/ijms21144983

Abstract

Platelet hyperactivation is involved in the established prothrombotic condition of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM) and familial hypercholesterolemia (HC), justifying the therapy with aspirin, a suppressor of thromboxane synthesis through the irreversible inhibition of cyclooxygenase-1 (COX-1), to prevent cardiovascular diseases. However, some patients on aspirin show a higher than expected platelet reactivity due, at least in part, to a pro-oxidant milieu. The aim of this study was to investigate platelet reactivity in T2DM (n = 103) or HC (n = 61) patients (aspirin, 100 mg/day) and its correlation with biomarkers of redox function including the superoxide anion scavenger superoxide dismutase (SOD) and the in vivo marker of oxidative stress urinary 8-iso-prostaglandin F2α. As results, in T2DM and HC subjects the prevalence of high on-aspirin platelet reactivity was comparable when both non-COX-1-dependent and COX-1-dependent assays were performed, and platelet reactivity is associated with a lower SOD activity that in a stepwise linear regression appears as the only predictor of platelet reactivity. To conclude, in T2DM and HC, similarly, the impairment of redox equilibrium associated with a decrease of SOD activity could contribute to a suboptimal response to aspirin.

Highlights

When subjects within each study population were stratified in high on‐aspirin platelet reactivity (HPR)+ and HPR- according to their response to CEPI Platelet Function Analyzer (PFA)-100 (Table 4), we found that HPR+ differed from HPR- for—(i) superoxide dismutase (SOD) activity (p = 0.002), soluble p-selectin (p = 0.001), soluble RAGE (sRAGE) (p = 0.004), and 11-dhTXB2 (p = 0.035) levels in HC patients; (ii) SOD activity (p = 0.0001), 8-iso-PGF2α (p < 0.0001), soluble CD40 Ligand (sCD40L) (p = 0.003), and 11-dhTXB2 (p = 0.042) in Type 2 Diabetes Mellitus (T2DM) patients
An impaired aspirin ability to inhibit platelet aggregation has been frequently observed in T2DM if compared with the general population [31,32], in this study we show that T2DM and primary HC patients, all on 100 mg/d aspirin treatment, display a similar prevalence for HPR+ in most of the in vitro assays used to test platelet sensitivity to the inhibitory effects of aspirin
To the best of our knowledge, we show for the first time that a high on-aspirin residual platelet reactivity based on CEPI PFA-100 method in both T2DM and HC patients is associated with a reduced activity of the extracellular SOD, a major extracellular antioxidant enzyme deeply involved in modulating the cell redox status and highly expressed in blood vessels, in arterial walls where it represents up to 70% of the total SOD activity [41]

Summary

Introduction

Atherothrombosis is the primary cause of cardio- and cerebrovascular events in patients with Type 2 Diabetes Mellitus (T2DM) and platelet hyperactivation plays a pivotal role in the initiation and progression of thrombotic complications that follow the atherosclerotic plaque disruption [1,2,3].Platelet activation is a multifactorial process where the platelet-platelet interaction provides a further source of intracellular signaling associated with the release of pro-inflammatory and proaggregating molecules, increasing the prothrombotic tendency.Since the inhibition of platelet activation pathways with antiplatelet therapy is crucial for the prevention of atherothrombotic diseases, aspirin (acetylsalicylic acid) has been extensively used as medication in the prevention of cardiovascular events in T2DM patients due to its main ability to suppress thromboxane A2 (TXA2) synthesis, a powerful activator of platelet response and thrombus formation, by irreversibly inhibiting cyclooxygenase-1 (COX-1) activity [4,5].in spite of its wide acceptance and utilization, the clinical aspirin effectiveness in protecting from vascular events has been questioned because of the occurrence of cerebro- and cardiovascular events even in the presence of low-dose aspirin treatment both in primary [4] and secondary prevention [5]. The role of biochemical and clinical features involved in the reduced aspirin effect in T2DM is a still debated issue—it has been shown that in T2DM patients, either genetic factors or secondary causes (metabolic disorders and/or inflammatory states) may be important contributors to the diminished aspirin action [6], demonstrating that the benefits of aspirin treatment may be overcome by aspirin-insensitive mechanisms of platelet activation [7,8]. As a result of the insufficient inhibition of COX-1 activity by aspirin, a larger amount of both serum and urinary excretion of TXA2 metabolites has been found and associated with increased incidence of major adverse cardiovascular events [9,10,11,12]

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