Analysis of Novel Mechanisms Underlying Aspirin Resistance using Bioinformatics Approach

Aspirin resistance is an increased risk factor for secondary vascular events, particularly in diabetic patients. It is defined by an inadequate inhibition of platelet aggregation with low dose of aspirin (75 to 81 mg). Aspirin is frequently prescribed as an anti-platelet aggregating agent. Currently, more than 30 million Americans are on chronic aspirin therapy. In spite of the benefits, many patients that are on aspirin therapy are still at risk for atherothrombotic complications due to aspirin resistance. Studies suggest that one in three patients with coronary heart disease may have resistance to antiplatelet therapy. Little is known on why aspirin resistance develops, but several studies have suggested that protein glycation could be a possible mechanism for such resistance. Aspirin exerts its antiplatelet aggregating effect by irreversibly acetylating cyclooxygenase-1 (Cox-I), thus preventing formation of thromboxane A2 in platelets. Another potential plasma protein that can be acetylated by aspirin is albumin, the most common plasma protein. In hyperglycemic patients, Cox-I and albumin are spontaneously glycated by blood glucose. The chronic glycated status of these proteins may cause aspirin resistance. Therefore, we hypothesize that glycation of Cox-I and albumin prevents their acetylation by aspirin, which leads to aspirin resistance. We employed bioinformatics tools to determine the putative glycation and acetylation sites of mammalian Cox-I and albumin and determined the amino acid residues that undergo glycation/acetylation. Based on the outcome, we propose that preventing the glycation of Cox-I and albumin will potentially help in recovery from aspirin resistance. This recovery directly correlates with a proper control of blood sugar levels. Understanding the mechanisms behind aspirin resistance is important to develop a strategy to counter it since such a resistance may increase thrombotic episodes in patients and pose a critical challenge to treat vascular diseases.