Sirolimus blocks the accumulation of hyaluronan (HA) by arterial smooth muscle cells and reduces monocyte adhesion to the ECM

Abstract 

Sirolimus (SRL), an inhibitor of human arterial smooth muscle cell (ASMC) proliferation and migration, prevents in-stent restenosis (ISR). Little is known about the effect of SRL on the extracellular matrix (ECM) component, hyaluronan, a key macromolecule in neointimal hyperplasia and inflammation. In this study, we investigated SRL regulation of the synthesis of hyaluronan by cultured human ASMC and the effect of SRL on hyaluronan mediated monocyte adhesion to the ECM. Hyaluronan production on a per cell basis was significantly inhibited by SRL at 4 days and remained so through 10 days. This reduction was correlated with reduced levels of hyaluronan synthase mRNAs while hyaluronan degradation rates were unchanged. Poly I:C, a viral mimetic, caused increased hyaluronan accumulation by ASMC cell layers and this increase was inhibited by SRL. The inhibition was paralleled by a reduction in hyaluronan-dependent monocyte adhesion to the ECM. This study demonstrates that SRL not only regulates the proliferation of ASMC but reduces the production of hyaluronan by these cells. This alteration in ECM composition results in reduced monocyte adhesion to the ECM in cultures of ASMC. Alterations in hyaluronan accumulation may contribute to the inhibition of ISR that is achieved by SRL.

Keywords: Restenosis, Arterial smooth muscle cells, Sirolimus, Hyaluronan, Monocytes