Acetylbritannilactone Inhibits Neointimal Hyperplasia after Balloon Injury of Rat Artery by Suppressing Nuclear Factor-κB Activation

Abstract

Based on our previous observations that 1-O-acetylbritannilactone (R)-4((3aS,4S,7aR)-4-hydroxy-6-methyl-3-methylene-2-oxo-2,3,3a,4,7,7a-hexahydrobenzofuran-5-yl)pentyl acetate (ABL) suppresses prostaglandin E 2 and nitric oxide synthesis in macrophages, the present study was designed to explore the effect of ABL on neointimal hyperplasia after balloon injury and its mechanism of action. In male Sprague-Dawley rats, 26 mg/kg ABL or polyglycol (control) was administered daily from 3 days before injury to 2 weeks after conventional balloon injury. ABL administration led to a significant reduction in neointimal formation (neointima to media ratio, 1.94 Ϯ 0.43 versus 0.84 Ϯ 0.29, P Ͻ 0.01) and proliferative activity of vascular smooth muscle cells after balloon injury in rats. Western blot analysis revealed that this is correlated to the inhibition of nuclear factor (NF)-B activation and to the reduced expression of cyclooxygenase-2. Investigation of potential signaling pathways demonstrated that ABL inhibited NF-B activation via the blockade of the inhibitor of NF-B kinase-␤ activation and the suppression of the degradation of the inhibitors of NF-B-␣. These findings suggest that ABL is a potential inhibitor of neointimal formation because it blocks injury-induced NF-B activation and may have beneficial effects in reducing the risk of restenosis after angioplasty.

Acetylbritannilactone Modulates MicroRNA-155-Mediated Inflammatory Response in Ischemic Cerebral Tissues

“…We found that ABL markedly inhibited the NF-κB and TLR4 expression induced by MCAO and OGD and increased the expression of MyD88, SOCS1 and I-κB. This is consistent with previous findings that ABL could suppress NF-κB activation and block the binding of active NF-κB to the target gene promoters (19)(20)(21). Our results suggest that ABL exerts its inhibitory effect on the ischemia-induced inflammation via abrogating the ischemia-induced upregulation of NF-κB and TLR4 and inducing the expression of MyD88, SOCS1 and I-κB.…”

“…Its chemical structure is different from ergolide, which was isolated previously (18). Several of the previous studies demonstrate that ABL inhibits the expression of inflammation-associated genes, such as the NOS and COX-2 genes, by reducing IκB-α phosphorylation and degradation, inhibiting NF-κB activation and blocking the binding of active NF-κB to the target gene promoters in RAW 264.7 macrophages and vascular smooth muscle cells (VSMCs) (19)(20)(21). In addition, ABL also can suppress PDGF-induced DNA synthesis and cell proliferation, subsequently leading to apoptosis in proliferative VSMCs via the induction of a higher ratio of Bax/Bcl-2, activation of caspase-9/-3 and the cleavage of the endogenous substrate Poly (ADP-ribose) polymerase (22).…”

Targeted Disruption of the Prostaglandin E 2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

“…In addition, although the effect of PGE 2 on VSMC proliferation has been reported by several groups, the results are inconsistent, with both inhibitory and stimulatory effects reported. [17][18]47,48 PGE 2 exerts its biological roles by 4 EP receptors, EP1 to EP4. Activation of EP receptors, with characteristic vascular distribution, evokes receptor-specific signaling pathways and results in distinct biological consequences.…”

Acetylbritannilactone suppresses growth via upregulation of kr�ppel-like transcription factor 4 expression in HT-29 colorectal cancer cells

“…Several proteins regulated by KLF4 such as p21, cyclin E are also targeted by ABL (4,24). Thus, we hypothesized that ABL may reduce proliferation by promoting the KLF4 activity.…”

“…1) and has been shown to possess anti-inflammatory and anticancer activities (4)(5)(6)(7)(8). Moreover, ABL has been shown to inhibit the expression of cyclooxygenase-2 (COX-2) that plays a significant role in colon carcinogenesis (9,10).…”