Inflachromene inhibits intimal hyperplasia through the HMGB1/2- regulated TLR4-NF-κB pathway

Abstract

The contractile-synthetic phenotypic conversion of vascular smooth muscle cells (VSMCs) plays a key role in atherosclerosis, vascular restenosis, and hypertension. Our previous study explored the correlation between high mobility group box protein (HMGB) 1 and HMGB2 and neointimal hyperplasia after vascular injury. In the present study, we explore whether inflachromene (ICM), a novel inhibitor of the expression of both HMGB1 and HMGB2, modulates phenotypic changes in VSMCs and the mechanisms involved. Mice treated with ICM after carotid artery wire injury showed a decrease in excessive neointimal hyperplasia compared with that in the vehicle groups. In cultured VSMCs, pretreatment with ICM suppressed the angiotensin II (Ang II)–induced phenotypic conversion, proliferation, and migration. We discovered that ICM reduced the Ang II–induced upregulation of the expression of HMGB1 and HMGB2 and inhibited their shuttling between the nucleus and the cytosol. Mechanistically, Ang II–treated VSMCs exhibited higher levels of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) phosphorylation, which were attenuated by ICM. In addition, the NF-κB inhibitor Bay-117082 abolished the recombinant HMGB1–mediated VSMC phenotypic conversion, proliferation, and migration. Furthermore, ICM ameliorated the Ang II–induced increases in NAD[P]H oxidase expression, thereby attenuating the Ang II–induced proliferation and migration. These results reveal that ICM pretreatment attenuates Ang II–induced VSMC dedifferentiation, proliferation, and migration may by regulating the TLR4-NF-kB pathway. Thus, ICM is a potential therapy and preventive treatment for vascular proliferative diseases.