Cilostazol attenuates MCP‐1 and MMP‐9 expression in vivo in LPS‐administrated balloon‐injured rabbit aorta and in vitro in LPS‐treated monocytic THP‐1 cells

Abstract

Monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) are involved in vascular inflammation. We tested the hypothesis, and explored the underlining mechanisms that cilostazol, a phosphodiesterase 3 inhibitor with antiplatelet and antithrombotic properties, inhibits lipopolysaccharide (LPS)-induced MCP-1 and MMP-9 expression. In a rabbit aorta balloon-injury model, administration of LPS increased macrophage infiltration and MCP-1 and MMP-9 expression; cilostazol supplementation prevented this phenomenon and reduced intimal hyperplasia. In contrast, the reverse zymography showed that cilostazol did not affect TIMP-1 expression in serum. In monocytic THP-1 cells, cilostazol and N6,O2'-dibutyryl-cAMP (dioctanoyl-cAMP, a cAMP analog) dose-dependently inhibited LPS-induced MCP-1 protein expression and MMP-9 activation, but did not affect the tissue inhibitor of metalloproteinase-1. Quantitative real-time polymerase chain reaction (PCR) showed that cilostazol inhibited MCP-1 and MMP-9 mRNA expression. Cilostazol significantly inhibited LPS-induced activation of p38, JNK, and nuclear factor-kappaB, and the respective inhibitors of p38 and JNK greatly reduced the level of LPS-induced MCP-1 and MMP-9, suggesting the involvement of the p38 and JNK pathways. In conclusion, cilostazol administered with LPS in vivo reduced neointimal hyperplasia and macrophage infiltration in the balloon-injured rabbit aorta; in vitro, cilostazol inhibits LPS-induced MCP-1 and MMP-9 expression. These data suggest that cilostazol may play an important role in preventing endotoxin- and injured-mediated vascular inflammation.

Cilostazol protects mice against endotoxin shock and attenuates LPS-induced cytokine expression in RAW 264.7 macrophages via MAPK inhibition and NF-κB inactivation: Not involved in cAMP mechanisms

“…Therefore, various efforts to design treatment strategies for sepsis have been focused on the elimination of the potentially detrimental pro-inflammatory mediators. It is well known that cilostazol increases intracellular cAMP levels by blocking its hydrolysis by PDE 3, resulting in suppressed inflammation [21]. We hypothesized that anti-inflammatory effects of cilostazol for the treatment of septic shock were via an increased intracellular cAMP level.…”

Cilostazol Reduces the Risk of Hemorrhagic Infarction After Administration of Tissue-Type Plasminogen Activator in a Murine Stroke Model

“…Our findings are consistent with a previous study demonstrating that cilostazol decreased MMP-9 expression in balloon-injured vasculature. 48 Cilostazol is known to raise the intracellular cAMP concentration in endothelial cells. In this context, cAMP promotes functional integrity of tight junctions between endothelial cells in the blood-brain barrier.…”

Cilostazol protects rat chondrocytes against nitric oxide–induced apoptosis in vitro and prevents cartilage destruction in a rat model of osteoarthritis

“…Cilostazol functions as a platelet aggregation inhibitor (15) and vasodilator (16), and is mainly used for treating patients with peripheral arterial disease (17) and intermittent claudication (18). In addition, it seems to reduce inflammation and inhibit MMP expression by increasing AMP and inhibiting the p38/ JNK pathway (19). Previous studies have demonstrated that cilostazol inhibits apoptosis under several circumstances (12,(20)(21)(22).…”