BACKGROUND: Platelet– endothelial interactions are thought to contribute to early atherogenesis. These interactions are po-tentiated by oxidative stress. We used in vivo molecular imaging to test the hypothesis that platelet– endothelial interactions occur at early stages of plaque development in obese, insulin-resistant nonhuman primates, and are suppressed by NADPH-oxidase-2 inhibition. METHODS AND RESULTS: Six adult rhesus macaques fed a Western-style diet for a median of 4.0 years were studied at baseline and after 8 weeks of therapy with the NADPH-oxidase-2-inhibitor apocynin (50 mg/kg per day). Six lean control animals were also studied. Measurements included intravenous glucose tolerance test, body composition by dual-energy X-ray absorpti-ometry, carotid intimal medial thickness, carotid artery contrast ultrasound molecular imaging for platelet GPIbα (glycoprotein-Ibα) and vascular cell adhesion molecule-1, and blood oxidative markers on mass spectrometry. Compared with lean controls, animals on a Western-style diet were obese (median body mass: 16.0 versus 8.7 kg, P=0.003; median truncal fat: 49% versus 20%, P=0.002), were insulin resistant (4-fold higher insulin– glucose area under the curve on intravenous glucose tolerance test, P=0.002), had 40% larger carotid intimal medial thickness (P=0.004), and exhibited oxidative signatures on proteomics. In obese but not lean animals, signal enhancement on molecular imaging was significantly elevated for GPIbα and vascular cell adhesion molecule-1. The signal correlated modestly with intimal medial thickness but not with the degree of insulin resist-ance. Apocynin significantly (P<0.01) reduced median signal for GPIbα by >80% and vascular cell adhesion molecule-1 signal by 75%, but did not affect intimal medial thickness, body mass, or intravenous glucose tolerance test results. CONCLUSION: In nonhuman primates, diet-induced obesity and insulin resistance leads to platelet– endothelial adhesion at early atherosclerotic lesion sites, which is associated with the expression of pro-inflammatory adhesion molecules. These responses appear to be mediated, in part, through oxidative pathways.
- Molecular imaging
- Von Willebrand factor
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine