Nonesterified Fatty Acids, Albumin, and Platelet Aggregation

Nonesterified Fatt y Acids, Albumin, and Platelet Aggregation Sandeep Dhindsa 1 2 Husam Ghanim 0 2 Paresh Dandona 0 2 0 Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo and Kaleida Health, Diabetes and Endocrinology Center of Western New York , Buffalo, NY 1 Division of Endocrinology and Metabolism, Texas Tech University Health Scien- ces Center , Permian Basin Campus, Odessa, TX 2 Dhindsa , Ghanim, and Dandona - It has been known for five decades that nonesterified fatty acids (NEFAs) have a role in the activation of platelets and thrombosis. Thus, the infusion of NEFAs leads to massive thrombosis and platelet activation (14). It has also been shown that their binding to albumin protects the platelets from activation (5). Thus, it follows that a fall in the concentrations of albumin, as in the nephrotic syndrome, would potentially lead to platelet activation. This has been demonstrated in several studies (6). Similarly, any condition that leads to an increase in NEFAs or a decrease in plasma albumin concentrations or a combination of the two would contribute to platelet hyperactivity. Insulin is a potent antilipolytic hormone and thus insulin-resistant states are characterized by accelerated lipolysis and increased NEFA concentrations. This promotes platelet aggregation. In addition, elevated NEFA concentrations interfere with insulin signal transduction and induce insulin resistance (7). NEFAs also induce oxidative and inflammatory stress (8) and thus activate monocytes, which express the prothrombotic tissue factor (TF) on their cell membranes (9). TF activates the extrinsic pathway of thrombin generation and hence may precipitate thrombosis. Activated platelets in patients with diabetes and peripheral vascular disease also release 5-hydroxytryptamine (5-HT), which leads to an increase in plasma 5-HT concentrations, which in turn promotes further vasoconstriction causing further platelet hyperaggregability (10). It is also important to emphasize the fact that as increased NEFAs induce insulin resistance, the action of insulin at the cellular and molecular level would also be reduced. Insulin exerts a potent antiplatelet effect (11), and the presence of insulin resistance would potentially enhance platelet aggregation. The antiplatelet effect of insulin is mediated by nitric oxide (NO) generated by intraplatelet NO synthase (12). Reactive oxygen species generated by the action of NEFAs would oxidize NO to its metabolites, peroxynitrite, NO2, and NO3. These actions of NEFA have already been shown to impair flowmediated vascular dilation within 2 h of their infusion (8). In addition, it has been shown that an increase in NEFA concentrations and a decrease in albumin concentrations reduce the stability of prostacyclin generated by the endothelium (13), which is a potent inhibitor of platelet aggregation and modulates platelet activity in the circulation. In addition, vascular ADPase activity, which inhibits ADP-induced platelet aggregation, is also inhibited by NEFAs (14). Thus, two potent antiplatelet modulators from vascular tissue are inhibited by NEFAs. NEFAs also inhibit prostacyclin production by aortic segments in vitro (15). In these three aspects, unsaturated fatty acids exert a significantly greater effect than saturated fatty acids. Following the demonstration that NEFAs induce oxidative and inflammatory stress, it was also shown that an infusion of NEFA results in a hypertensive effect (16). Such an effect would promote atherogenesis. Thus, NEFAs induce several effects detrimental to platelet function and cardiovascular health. It is in the context of these previous observations that Blache et al. (17) have now investigated the paradigm that the glycation or glycoxidation of albumin is relevant to NEFA-related pathophysiology as such modifications of albumin would potentially result in an impaired binding to NEFAs and an increase in unbound NEFAs and thus to platelet hyperactivity. The authors have shown that glycation of albumin induced in vitro with glucose or methylglyoxal, an advanced glycation end product, leads to Figure 1Role of NEFAs in prothrombotic state in insulin resistance and diabetes. eNOS, endothelial nitric oxide synthase. a reduction in the binding of NEFA to albumin; these changes were similar to those observed in albumin prepared from patients with diabetes. The NEFA binding capacity of albumin isolated from patients with diabetes was lower by 32%. In addition, there were similarities in structural changes induced in vitro to those observed in albumin obtained from patients with diabetes, as analyzed with sophisticated fluorescence techniques. An increase in NEFA concentrations promotes the oxidation of the Cys34 in the albumin molecule and consequent reduction of albumins antioxidant capacity, which leads to a further decrease in NEFA binding sites and the activation of platelets. Such activated platelets lead to a great (...truncated)