Proinflammatory Endothelial Activation Detected by Molecular Imaging in Obese Nonhuman Primates Coincides With Onset of Insulin Resistance and Progressively Increases With Duration of Insulin Resistance

Abstract

Background Inflammation and insulin resistance (IR) are associated processes that potentiate risk for cardiovascular disease in obesity. The temporal relation between IR and inflammation is not completely characterized. We hypothesized that endothelial cell adhesion molecule (ECAM) expression in large arteries is an early event that coincides with diet-induced obesity and IR in primates. Methods and Results Ten adult male rhesus macaques were studied at baseline and every 4-6 months on high-fat diet (HFD) for 2 years. Truncal fat, carotid intima-media thickness (IMT), plasma inflammatory biomarkers, and carotid P-selectin and VCAM-1 expression by contrast-enhanced ultrasound molecular imaging were assessed. Intravenous glucose tolerance test (IVGTT) was performed at baseline, 4 and 18 months. HFD produced a rapid increase (p<0.01) in weight, truncal fat, and degree of IR indicated by the insulin area-under-the-curve and glucose disappearance rate on IVGTT; all of which worsened minimally thereafter. Molecular imaging detected a progressive increase in ECAM expression over time (5-7-fold greater than control agent signal at 2 yrs, p<0.01). Changes in IMT were not detected until 2 years and, while there was a trend toward an increase in plasma markers of inflammation (MCP-1, CRP), the pattern of increase varied considerably over time. Conclusions In primates with diet-induced obesity, endothelial inflammatory activation is an early event that occurs coincident with the development of IR and long before any measurable change carotid IMT. Endothelial activation is more related to the duration rather than severity of IR and is not mirrored by changes in plasma biomarkers.

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

“…Next to pigs, the expression of P-selectin and VCAM-1 expression in the carotid of non-human primates has also been recently assessed with UMI. This study shows that endothelial cell adhesion molecule expression in large arteries could be an early event that coincides with diet-induced obesity and insulin resistance in non-human primates [174]. In another recent study on non-human primates with myocardial ischaemia, UMI was shown to be both safe and effective for imaging recent myocardial ischaemia.…”

Molecular Imaging of Platelet–Endothelial Interactions and Endothelial von Willebrand Factor in Early and Mid-Stage Atherosclerosis

“…A low level of non-targeted lipid MB signal due to complement-mediated interactions with leukocytes or endothelial cells has been detected in many previous CEU molecular imaging studies of atherosclerosis in murine models but not in our recent studies performed in a non-human primate model. 9,13,38 As mentioned previously, the issue of control MB signal confounded interpretation of the temporal increase in platelet signal since age-dependent increase in MB-A1 was highly significant when expressed as a difference between control MB but not when expressed as a ratio.…”

Protective Effects of Oxymatrine on Vascular Endothelial Cells from High-Glucose-Induced Cytotoxicity by Inhibiting the Expression of A2B Receptor

“…Vascular endothelial cells are involved in inflammation and immune response by secreting a series of bioactive substances, such as prostacyclin, NO, endothelin and von Willebrand factor [22]. In addition to the formation of NO which promotes vasodilation, endothelial cells also modulate the migration of leukocytes through releasing inflammatory chemokines, cytokines, and cell surface adhesion molecules [23]. Inflammation, trauma and other stress injuries stimulate endothelial cells to increase vascular permeability and adhesion molecule expression, leading to edema, adhesion of leukocytes, and a subsequent inflammatory cascade reaction [24].…”