Arterial Platelet Adhesion in Atherosclerosis-Prone Arteries of Obese, Insulin-Resistant Nonhuman Primates

• Published in: Journal of the American Heart Association Vol. 10; no. 9; p. e019413
• Main Authors: Brown, Eran, Ozawa, Koya, Moccetti, Federico, Vinson, Amanda, Hodovan, James, Nguyen, The Anh, Bader, Lindsay, López, José A, Kievit, Paul, Shaw, Gray D, Chung, Dominic W, Osborn, Warren, Fu, Xiaoyun, Chen, Junmei, Lindner, Jonathan R
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 04.05.2021; Wiley
• Subjects: atherosclerosis; molecular imaging; Original Research; platelets; von Willebrand factor; atherosclerosis; molecular imaging; von Willebrand factor; platelets
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.120.019413

Background Platelet-endothelial interactions are thought to contribute to early atherogenesis. These interactions are potentiated 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 absorptiometry, 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, =0.003; median truncal fat: 49% versus 20%, =0.002), were insulin resistant (4-fold higher insulin-glucose area under the curve on intravenous glucose tolerance test, =0.002), had 40% larger carotid intimal medial thickness ( =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 resistance. Apocynin significantly ( <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.