Effect of Proteasome Inhibitor on Vascular Cell Adhesion Molecule-1 (VCAM-1) and Intercellular Adhesion Molecule-1 (ICAM-1) Expressions in Rat Model of Atherosclerosis

Abstract

Background:The effect of proteasome inhibitors on atherosclerosis is known to vary depending on the atherosclerosis stage. Previous studies have shown that the highest proteasome expression in atherosclerotic lesions is at the progression stage. Adhesion molecules play a role in the progression stage of atherosclerosis, but no studies have analyzed the effect of proteasome inhibitors on the expression of adhesion molecules at this stage. Methods: This experimental study aimed to analyze the effect of a proteasome inhibitor, namely bortezomib, on the vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule1 (ICAM-1) expressions in blood vessels of rat model of atherosclerosis at the progression stage. This study used 18 male Wistar rats divided into three groups, i.e. group I that is the control group given standard feed, group II induced by atherosclerosis, and group III induced by atherosclerosis and given bortezomib. Atherosclerosis induction was performed using vitamin D3 (700,000 IU/kg) orally by gastric intubation on the 1 st day and atherogenic feed given for four days. Bortezomib 50 µg/kgBW/day was administered intra-peritoneally. The expression of VCAM-1 and ICAM-1 molecules was measured using immunohistochemistry and analyzed quantitatively using Adobe Photoshop software. Results: The statistical test showed differences in VCAM-1 expression between atherosclerosis + Bortezomib group and atherosclerosis group, but there were no differences in the expression of ICAM-1 and atherosclerotic lesions between the groups. Conclusions: Administration of bortezomib 50μg/kg for four days in progressive atherosclerosis model rats can inhibit VCAM-1 expression, although it does not affect ICAM-1 expression and cannot inhibit atherosclerotic lesion formation.

Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1–directed novel therapeutics

“…Wilck et al 73 found that administration of low-dose bortezomib significantly reduced VCAM-1 expression, macrophage infiltration, and early atherogenesis in LDLR −/− mice. However, this research was opposed in a later study by Ismawati et al , 72 which demonstrated that a short-term dosage regimen of bortezomib did not suppress atherosclerotic lesion formation in atherogenic Wistar rat models despite reducing VCAM-1 expression. Another concern is the occurrence of adverse CVD events that have been observed in existing clinical studies with multiple myeloma patients.…”

Coronary atherosclerosis and chemotherapy: From bench to bedside

“…The results showed that substantial proteasome inhibition is associated with increased oxidative stress, impaired coronary endothelium-dependent vasodilation, and intimal thickening, exacerbating the vascular effects of traditional cardiovascular risk factors such as hypercholesterolemia ( 11 ). Notably, Ismawati et al ( 87 ) found that proteasome inhibitors reduced early arteriosclerosis in low density lipoprotein receptor (LDLR) mice, this suggests that proteasome inhibitors inhibit the formation of early arteriosclerosis lesions ( 87 ). However, the effect of proteasome inhibitors on coronary atherosclerosis remains controversial.…”