Deletion of Smooth Muscle Lethal Giant Larvae 1 Promotes Neointimal Hyperplasia in Mice.

Ya Zhang,Qiming Deng,Peidong Yuan,Jianmin Yang,Cheng Zhang,Tianran Zhang,Wencheng Zhang,Jiangang Gao,Xiaoping Ma

doi:10.3389/fphar.2022.834296

Abstract

Vascular smooth muscle cell (VSMC) proliferation and migration contribute to neointimal hyperplasia after injury, which causes vascular remodeling related to arteriosclerosis, hypertension, and restenosis. Lethal giant larvae 1 (LGL1) is a highly conserved protein and plays an important role in cell polarity and tumor suppression. However, whether LGL1 affects neointimal hyperplasia is still unknown. In this study, we used smooth muscle-specific LGL1 knockout (LGL1SMKO) mice generated by cross-breeding LGL1flox/flox mice with α-SMA-Cre mice. LGL1 expression was significantly decreased during both carotid artery ligation in vivo and PDGF-BB stimulation in vitro. LGL1 overexpression inhibited the proliferation and migration of VSMCs. Mechanistically, LGL1 could bind with signal transducer and activator of transcription 3 (STAT3) and promote its degradation via the proteasomal pathway. In the carotid artery ligation animal model, smooth muscle-specific deletion of LGL1 accelerated neointimal hyperplasia, which was attenuated by the STAT3 inhibitor SH-4-54. In conclusion, LGL1 may inhibit neointimal hyperplasia by repressing VSMC proliferation and migration via promoting STAT3 proteasomal degradation.

Highlights

Neointimal hyperplasia is a significant type of vascular remolding defined as the pathological accumulation of vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) in the intima
To explore the relation between Lethal giant larvae 1 (LGL1) level and vascular injury, we examined the expression of LGL1 in the mouse model of neointimal hyperplasia
The LGL1 level was related to vascular injury, which suggests that LGL1 may be involved in the development of neointimal hyperplasia

Summary

INTRODUCTION

Neointimal hyperplasia is a significant type of vascular remolding defined as the pathological accumulation of vascular smooth muscle cells (VSMCs) and extracellular matrix (ECM) in the intima. It is a process of excessive repair in the vascular wall caused by various activated cells and recycling substances responding to vessel injury (Zaman and Herath, 2008). LGL1 Inhibits Neointimal Hyperplasia migration from the media layer of the vessel to the intima (Dzau et al, 1991; Majesky et al, 1991; Nabel et al, 1993; Grant et al, 1994; Dzau et al, 2002). We found that LGL1 could inhibit neointimal hyperplasia after injury via STAT3

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DISCUSSION

ETHICS STATEMENT