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

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

doi:10.3389/fphar.2022.834296

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

Front Pharmacol. 2022 Jan 24:13:834296. doi: 10.3389/fphar.2022.834296. eCollection 2022.

Authors

Ya Zhang¹, Peidong Yuan^{1

2}, Xiaoping Ma³, Qiming Deng¹, Jiangang Gao⁴, Jianmin Yang¹, Tianran Zhang⁵, Cheng Zhang¹, Wencheng Zhang^{1

2}

Affiliations

¹ The Key Laboratory of Cardiovascular Remodeling and Function Research, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
³ Department of Obstetrics and Gynecology, Liaocheng People's Hospital, Liaocheng, China.
⁴ School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, China.
⁵ Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

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 (LGL1^SMKO) mice generated by cross-breeding LGL1^flox/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.

Keywords: LGL1; STAT3; neointimal hyperplasia; proteasomal degradation; smooth muscle.