Invited commentary

Abstract

Neointimal hyperplasia (NIH) is the proliferation and migration of vascular smooth muscle cells primarily in the intima, resulting in the thickening of the arterial wall and decreased arterial lumen. NIH is a significant problem after revascularization that can lead to significant graft and stent failures. Novel research investigating pathways that are responsible for NIH may provide insight into the pathophysiologic process and effective treatment options. There are currently drug-eluting stents based on paclitaxel and sirolimus, which are designed to inhibit smooth muscle cell proliferation. Although they are effective at reducing NIH, in-stent restenosis and thrombosis continue to occur. This may be due to the nonspecific effects of the drug to the target pathways/cells or incomplete inhibition of the pathways responsible for NIH. In this very important study, the authors investigate the inhibition of Rho GTPase, specifically RhoA and its effect on Hippo pathway-related genes and YAP transcription coactivator. YAP (Yes-associated protein) is a protein that acts as a transcriptional regulator by activating the transcription of genes involved in cell proliferation and suppressing apoptotic genes. Initially, the study demonstrated that active RhoA expression affects the smooth muscle cell synthetic phenotype and decreases the contractile phenotype. Inhibition of RhoA by rhosin decreased cell proliferation but had no effect on apoptosis. The inhibition of RhoA-guanosine triphosphate involved the knockdown of cyclin D and affected the majority of cells in the S phase of the cell cycle. Next, the authors demonstrated that YAP plays an important role in the regulation of smooth muscle cell phenotypic modulation and is affected by RhoA, whereby RhoA inhibition reduces the expression of both cytoplasmic and nuclear YAP. Finally, the authors tested whether inhibition of RhoA in a carotid rabbit model would decrease NIH, using rhosin jelly-coated stents to inhibit RhoA. Compared with bare-metal stents, the rhosin-coated stents had less NIH, and cellular analysis demonstrated that the smooth muscle cell contractile phenotype was induced and the synthetic phenotype was suppressed. These effects were mitigated when active YAP lentivirus was instilled into the RhoA-inhibited stent carotid section for 30 minutes, indicating the involvement of YAP in switching the smooth muscle cell phenotype from contractile to synthetic, with increased NIH. In summary, the data demonstrated that the RhoA inhibitor-eluting stent attenuated in-stent restenosis through the YAP signaling pathway evaluated at 6 months. These novel mechanistic discoveries of RhoA and YAP involved in NIH in the context of arterial stents offer an exciting and promising area for clinical trials using RhoA inhibitor drug-eluting stents. Further work is necessary to validate the in vitro and in vivo animal studies from this study, to translate the basic scientific research of RhoA inhibition and decreased NIH, and to determine the effectiveness and durability in human trials. The opinions or views expressed in this commentary are those of the author and do not necessarily reflect the opinions or recommendations of the Journal of Vascular Surgery or the Society for Vascular Surgery. RhoA inhibitor-eluting stent attenuates restenosis by inhibiting YAP signalingJournal of Vascular SurgeryVol. 69Issue 5PreviewCurrent drug-eluting stent (DES) treatment is promising, but it still has the drawback of in-stent restenosis, which remains a clinically relevant problem. Efforts should be made to discover new signaling molecules and novel potential targets for the prevention of arterial restenosis. In this study, we fabricated a novel DES targeting the RhoA pathway and further examined this promising strategy in vitro and in a rabbit carotid model. Full-Text PDF Open Archive