Linarin Ameliorates Restenosis After Vascular Injury in Type 2 Diabetes Mellitus via Regulating ADAM10-Mediated Notch Signaling Pathway

Aihua Jiang; Lin Liu; Jianping Wang; Yinglan Liu; Shanshan Deng; Tao Jiang

doi:10.1007/s12012-024-09863-4

Linarin Ameliorates Restenosis After Vascular Injury in Type 2 Diabetes Mellitus via Regulating ADAM10-Mediated Notch Signaling Pathway

Cardiovasc Toxicol. 2024 May 1. doi: 10.1007/s12012-024-09863-4. Online ahead of print.

Authors

Aihua Jiang¹, Lin Liu², Jianping Wang¹, Yinglan Liu¹, Shanshan Deng¹, Tao Jiang³

Affiliations

¹ Department of Endocrinology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, No. 35 Jiefang Road, Zhengxiang District, Hengyang, 421001, Hunan Province, China.
² Department of Gastroenterology, Hengyang Central Hospital, Hengyang, 421001, China.
³ Department of Endocrinology, The Second Affiliated Hospital, Hengyang Medical School, University of South China, No. 35 Jiefang Road, Zhengxiang District, Hengyang, 421001, Hunan Province, China. qq505142506@163.com.

PMID: 38691303
DOI: 10.1007/s12012-024-09863-4

Abstract

Vascular lesions frequently arise as complication in patients diagnosed with diabetes mellitus (DM). Presently, percutaneous coronary intervention (PCI) and antithrombotic therapy serve as primary treatments. However, in-stent restenosis persists as a challenging clinical issue following PCI, lacking sustained and effective treatment. Linarin (LN) exhibits diverse pharmacological activities and is regarded as a potential drug for treating various diseases, including DM. But its specific role in restenosis after vascular injury in DM patients remains unclear. A rat model of diabetes-related restenosis was established to evaluate the role of LN on neointimal hyperplasia. Vascular smooth muscle cells (VSMCs) stimulated by high glucose (HG, 30 mM) underwent LN treatment. Additionally, an overexpression plasmid of A disintegrin and metalloproteinases (ADAM10) was constructed to transfect VSMCs. We employed CCK-8, Brdu, wound-healing scratch, and transwell migration assays to evaluate the proliferation and migration of VSMCs. Furthermore, western blot and immunofluorescence assays were utilized to investigate the expressions of ADAM10 and the downstream Notch signaling pathway in vivo and in vitro models. LN notably alleviated intimal hyperplasia after vascular injury in DM rats and reduced the protein expression of ADAM10, alongside its downstream Notch1 signaling pathway-related proteins (Notch1, NICD and Hes1) in rat carotid artery tissues. LN effectively suppressed the proliferation and migration of VSMCs induced by HG, downregulating the protein expression of ADAM10, Notch1, NICD and Hes1. Moreover, our findings indicated that ADAM10 overexpression significantly reversed LN's effects on proliferation, migration, and the expression of Notch1 signaling pathway-related proteins in HG-treated VSMCs. LN demonstrates potential therapeutic efficacy in addressing restenosis after diabetic-related vascular injury, with the ADAM10 mediated Notch signaling pathway playing a pivotal role.

Keywords: ADAM10; Linarin; Notch signaling pathway; Restenosis after vascular injury; Type II diabetes mellitus.