Endothelial Function and Dipper Status

SUMMARY Aims: Essential hypertension, as well as other established cardiovascular risk factors, is associated with endothelial dysfunction. Hypertensive patients with a nondipper circadian pattern have a greater risk of cerebrovascular and cardiovascular complications in comparison with those with a dipper circadian pattern. In this study, we evaluated the association between nondipper pattern and endothelial function in patients with essential hypertension. Methods: We evaluated the forearm blood flow (FBF) response to intraarterial acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, infusions in 190 hypertensive patients stratified according to dipper and nondipper status. The FBF was measured by strain-gauge plethysmography. Effects of oxidative stress on FBF were evaluated by intraarterial infusion of vitamin C. Ambulatory BP monitorings were obtained by a validated oscillometric device (SpaceLabs 90207 Monitor Inc., Issaquah, WA, USA). Results: Systolic and diastolic blood pressures were higher during daytime and lower during night-time in dipper subjects than in nondippers. The peak percent increase in ACh-stimulated FBF was higher in dippers than in nondippers (473% vs. 228%, P < 0.001). The FBF responses to SNP were similar in dipper and nondipper patients. The FBF response to ACh during coinfusion of vitamin C was higher in nondippers rather than in dipper hypertensives. Conclusions: Present data demonstrate that endothelium-dependent vasodilation is impaired in patients who have nondipper hypertension. The effects of vitamin C on impaired ACh-stimulated vasodilation support the hypothesis that oxidative stress contributes to endothelial dysfunction of nondipper hypertensive patients

Uric Acid Impairs Insulin Signaling by Promoting Enpp1 Binding to Insulin Receptor in Human Umbilical Vein Endothelial Cells

High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (IR) and it is overexpressed in insulin-resistant subjects. In keeping with this, we stimulated human umbilical vein endothelial cells (HUVECs) with insulin and UA to investigate the effects of UA on insulin signaling pathway, testing the hypothesis that UA can interfere with insulin signaling by the activation of ENPP1. Cultures of HUVECs were stimulated with insulin, UA and the urate transporter SLC22A12 (URAT1) inhibitor probenecid. Akt and endothelial nitric oxide synthase (eNOS) phosphorylation levels were investigated by immunoblotting. ENPP1 binding to IR and its tyrosine phosphorylation levels were tested by immunoprecipitation and immunoblotting. UA inhibited insulin-induced Akt/eNOS axis. Moreover, UA induced ENPP1 binding to IR that resulted in an impairment of insulin signaling cascade. Probenecid reverted UA effects, suggesting that UA intracellular uptake is required for its action. In endothelial cells, UA directly interferes with insulin signaling pathway at receptor level, through ENPP1 recruitment. This evidence suggests a new molecular model of UA-induced insulin resistance and vascular damage