Abstract
Diabetes is associated with endothelial dysfunction and platelet activation, both of which may contribute to increased cardiovascular risk. The purpose of this study was to characterize circulating platelets in diabetes and clarify their effects on endothelial function. Male Wistar rats were injected with streptozotocin (STZ) to induce diabetes. Each experiment was performed by incubating carotid arterial rings with platelets (1.65×107 cells/mL; 30 min) isolated from STZ or control rats. Thereafter, the vascular function was characterized in isolated carotid arterial rings in organ bath chambers, and each expression and activation of enzymes involved in nitric oxide and oxidative stress levels were analyzed. Endothelium-dependent relaxation induced by acetylcholine was significantly attenuated in carotid arteries treated with platelets isolated from STZ rats. Similarly, treatment with platelets isolated from STZ rats significantly reduced ACh-induced Akt/endothelial NO synthase signaling/NO production and enhanced TXB2 (metabolite of TXA2), while CD61 (platelet marker) and CD62P (activated platelet marker) were increased in carotid arteries treated with platelets isolated from STZ rats. Furthermore, the platelets isolated from STZ rats decreased total eNOS protein and eNOS dimerization, and increased oxidative stress. These data provide direct evidence that circulating platelets isolated from diabetic rats cause dysfunction of the endothelium by decreasing NO production (via Akt/endothelial NO synthase signaling pathway) and increasing TXA2. Moreover, activated platelets disrupt the carotid artery by increasing oxidative stress.
Highlights
Diabetes mellitus is associated with the accelerated development of cardiovascular diseases which are the primary cause of morbidity and mortality in patients [1,2,3,4]
It has been well established that the pathogenesis and progression of vascular complications of diabetes are characterized by the development of endothelial dysfunction, which correlates with a decrease in vasodilator factor release, such as nitric oxide (NO) or prostacyclin, as well as an increase in vasoconstrictor production, such as Thromboxane A2 (TXA2) [1,5,6,7,8]
We demonstrated that activated PLTs impair the endothelial function and increase levels of oxidative stress, suggesting that decreased NO bioavailability and increased vasoconstriction contribute to the effects of PLTs in diabetes
Summary
Diabetes mellitus is associated with the accelerated development of cardiovascular diseases which are the primary cause of morbidity and mortality in patients [1,2,3,4]. It has been well established that the pathogenesis and progression of vascular complications of diabetes are characterized by the development of endothelial dysfunction, which correlates with a decrease in vasodilator factor release, such as nitric oxide (NO) or prostacyclin, as well as an increase in vasoconstrictor production, such as Thromboxane A2 (TXA2) [1,5,6,7,8]. NO generated from endothelial NO synthase (eNOS) plays a key role in vascular homeostasis. At the cellular level and in isolated blood vessels, it has been well established that ACh increases NO production by activating the Akt signaling pathway that leads to eNOS phosphorylation [5]. Several studies have shown that oxidative stress plays a determinant role in the reduced effect of endothelial NO and this may occur in the vasculature in diabetes [11]. Oxidative stress is known to reduce the biological activity of NO and generate deleterious metabolites such as peroxynitrite [12,13]
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