Cilostazol Protects Diabetic Rats from Vascular Inflammation via Nuclear Factor-κB-Dependent Down-Regulation of Vascular Cell Adhesion Molecule-1 Expression

Abstract

Vascular cell adhesion molecule (VCAM)-1 plays a critical role in the initiation and development of vascular inflammation and selective inhibition of adhesion molecules expressed by endothelial cells may present a new therapeutic strategy for the treatment of vascular complications associated with diabetes mellitus. Increasing evidence indicates that cilostazol, a cAMP phosphodiesterase inhibitor, reduces VCAM-1 expression on endothelial cells. In this study, we have tested the effect of cilostazol on the development of vascular inflammation in rats with streptozotocin-induced diabetes and determined the mechanism by which cilostazol prevents diabetes-induced vascular inflammation in the aorta. Diabetic rats were treated with different dose of cilostazol (27 or 9 mg/kg/day) for 8 weeks, and aortae were removed for the evaluation of vascular inflammation. The VCAM-1 protein expression and VCAM-1 mRNA transcripts were analyzed by immunohistochemical staining and in situ hybridization assay, respectively. Our results demonstrated that cilostazol treatment prevents the overexpression of VCAM-1 and protects diabetic rats from vascular inflammation. More importantly, our mechanistic studies suggested that cilostazol controls the VCAM-1 overexpression via inhibiting the activation of nuclear factor-B.

Effect of cilostazol in treating diabetes-associated microvascular complications

“…Treatment with cilostazol significantly reduced the inflam-matory marker highly-sensitive C-reactive protein (p = 0.03), endothelial markers E-selectin (p < 0.001) and solu-ble vascular cell adhesion molecule-1 (p < 0.001). Results of the study suggest that renal deterioration resulting from an upregulated immune response mediated by NF-ĸB-induced inflammatory and endothelial markers may be suppressed with cilostazol by inhibiting NF-ĸB [15][16][17]. Additionally, as supported by another study, cilostazol may ameliorate peripheral arterial occlusion disease, a macro-vascular complication of diabetes mellitus, in patients with type 2 diabetes mellitus by attenuating pro-inflammatory markers [18].…”

The Renal Protective Effects of Cilostazol on Suppressing Pathogenic Thrombospondin-1 and Transforming Growth Factor-β Expression in Streptozotocin-Induced Diabetic Rats

“…7 Cilostazol has also been shown to protect diabetic rats from vascular inflammation. 8 Research has shown that cilostazol inhibits protein kinase C (PKC) activity at the phosphoinositide-3 (PI-3) kinase level, which suppresses nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation in the presence of phorbol 12-myristate 13-acetate (PMA) or tumour necrosis factor (TNF)-α. 9 By inhibiting the PI-3 kinasedependent pathway, cilostazol prevents the oxidative stress caused by the NADPHinduced release of reactive oxygen species, which may protect against the development of diabetic nephropathy.…”

Alteration in Inflammation-related miR-146a Expression in NF-KB Signaling Pathway in Diabetic Rat Hippocampus

“…12 Expression of a large number of inflammation proteins is increased via NF-KB. 20 In contrast to many studies done about the role of NF-KB in different systems like the immune system, there are a few studies on the role of NF-KB in the nervous system. NF-KB is expressed in neurons and glial cells in central and peripheral nervous systems.…”