Arterial platelet adhesion in atherosclerosis-prone arteries of obese, insulin-resistant nonhuman primates

Eran Brown, Koya Ozawa, Federico Moccetti, Amanda Vinson, James Hodovan, The Anh Nguyen, Lindsay Bader, José A. López, Paul Kievit, Gray D. Shaw, Dominic W. Chung, Warren Osborn, Xiaoyun Fu, Junmei Chen, Jonathan R. Lindner

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere019413
JournalJournal of the American Heart Association
Volume10
Issue number9
DOIs
StatePublished - 2021

Keywords

  • Atherosclerosis
  • Molecular imaging
  • Platelets
  • Von Willebrand factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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