Abstract 044: Platelet-Endothelial Interactions in Atherosclerosis-Prone Arteries in a Non-Human Primate Model of Obesity and Insulin Resistance

Abstract

Background: Platelet interactions with the vascular endothelium contribute to early atherogenesis, and occur in part from oxidative stress and secondary dysregulation of endothelial-associated von Willebrand factor (VWF). We used in vivo contrast enhanced ultrasound (CEU) molecular imaging of the carotid endothelium in a non-human primate model of diet-induced obesity to test whether platelet adhesion is present in atherosclerosis-susceptible arteries prior to plaque development, and whether it can be modified through NADPH-oxidase (Nox) inhibition. Methods: Six adult rhesus macaques fed a high-fat diet (HFD), with 30% of calories from fat, for >2 years were studied at baseline and after 8 weeks of therapy with the Nox inhibitor apocynin (50 mg/kg/d). Six lean chow-fed controls were also studied. Intravenous glucose tolerance tests (IVGTT) and body composition were assessed at each interval. CEU molecular imaging of VCAM-1 and platelet GPIbα of the carotid arteries bilaterally was used to assess endothelial activation and platelet adhesion. Carotid intimal thickening (IMT) and brachial flow-mediated dilation (FMD) were assessed by ultrasound. Results: Before therapy, animals on HFD compared to controls were obese (16.0 vs 9.3 kg, p=0.003), had increased visceral adiposity (49% vs 25% truncal fat, p=0.002), and were insulin resistant (4-fold higher insulin AUC on IVGTT, p=0.002). FMD and IMT were similar between cohorts, although mild plaque was seen in the carotid bulb in 3 HFD macaques. HFD animals had greater (p<0.01 vs. controls) carotid CEU signal for VCAM-1 (20.0 vs -2.7 IU) and GPIbα (12.7 vs -0.4 IU). There was a linear correlation between VCAM-1 and GP1ba signal (r 2 =0.50, p=0.0001). Apocynin significantly reduced (p<0.01 vs pre-treatment) signal for VCAM-1 (3.96 IU) and GPIbα (0.19 IU); but did not alter IMT, FMD, visceral adiposity, or insulin resistance on IVGTT. Conclusions: Platelet- endothelial interactions occur early in atherosclerosis-prone carotid arteries of obese and insulin resistant non-human primates, and correlates with the degree of endothelial adhesion molecule expression. Inhibition of Nox suppresses platelet adhesion and reduces VCAM-1 expression independent of any effects on insulin resistance and obesity.