Journal
JOURNAL OF THE AMERICAN HEART ASSOCIATION
Volume 10, Issue 9, Pages -Publisher
WILEY
DOI: 10.1161/JAHA.120.019413
Keywords
atherosclerosis; molecular imaging; platelets; von Willebrand factor
Categories
Funding
- National Institutes of Health [R01-HL078610, R01-HL130046, P51-OD011092, R35-HL145262, R01-HL137991]
- Japanese Society for the Promotion of Science Overseas Research Fellowship
- Manpei Suzuki Diabetes Foundation Award
- Swiss National Science Foundation
- NIH [P51OD011092]
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In obese and insulin-resistant nonhuman primates, platelet-endothelial adhesion occurs at early atherosclerotic lesion sites, associated with expression of pro-inflammatory adhesion molecules. These responses are partly mediated through oxidative pathways.
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 GPIb alpha (glycoprotein- Ib alpha) 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 GPIb alpha and vascular cell adhesion molecule-1. The signal correlated modestly with intimal medial thickness but not with the degree of insulin resistance. Apocynin significantly (P<0.01) reduced median signal for GPIb alpha 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.
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