Mindin regulates vascular smooth muscle cell phenotype and prevents neointima formation.

Abstract

Mindin/spondin 2, an extracellular matrix (ECM) component that belongs to the thrombospondin type 1 (TSR) class of molecules, plays prominent roles in the regulation of inflammatory responses, angiogenesis and metabolic disorders. Our most recent studies indicated that mindin is largely involved in the initiation and development of cardiac and cerebrovascular diseases [Zhu et al. (2014) J. Hepatol. 60, 1046-1054; Bian et al. (2012) J. Mol. Med. 90, 895-910; Wang et al. (2013) Exp. Neurol. 247, 506-516; Yan et al. (2011) Cardiovasc. Res. 92, 85-94]. However, the regulatory functions of mindin in neointima formation remain unclear. In the present study, mindin expression was significantly down-regulated in platelet-derived growth factor-BB (PDGF-BB)-stimulated vascular smooth muscle cells (VSMCs) and wire injury-stimulated vascular tissue. Using a gain-of-function approach, overexpression of mindin in VSMCs exhibited strong anti-proliferative and anti-migratory effects on VSMCs, whereas significant suppression of intimal hyperplasia was observed in transgenic (TG) mice expressing mindin specifically in smooth muscle cells (SMCs). These mice exhibited blunted VSMC proliferation, migration and phenotypic switching. Conversely, deletion of mindin dramatically exacerbated neointima formation in a wire-injury mouse model, which was further confirmed in a balloon injury-induced vascular lesion model using a novel mindin-KO (knockout) rat strain. From a mechanistic standpoint, the AKT (Protein Kinase B)-GSK3β (glycogen synthase kinase 3β)/mTOR (mammalian target of rapamycin)-FOXO3A (forkhead box O)-FOXO1 signalling axis is responsible for the regulation of mindin during intimal thickening. Interestingly, an AKT inhibitor largely reversed mindin-KO-induced aggravated hyperplasia, suggesting that mindin-mediated neointima formation is AKT-dependent. Taken together, our findings demonstrate that mindin protects against vascular hyperplasia by suppression of abnormal VSMC proliferation, migration and phenotypic switching in an AKT-dependent manner. Up-regulation of mindin might represent an effective therapy for vascular-remodelling-related diseases.

• Authors: Li-Hua Zhu, Ling Huang, Xiaojing Zhang, Peng Zhang, Shu-Min Zhang, Hongjing Guan, Yan Zhang, Xue-Yong Zhu, Song Tian, Keqiong Deng, Hongliang Li
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 129 Issue 2 Pg. 129-45 (Jul 2015) ISSN: 1470-8736 [Electronic] England
• PMID: 25751394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Extracellular Matrix Proteins
• Protein Kinase Inhibitors
• mindin
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Gsk3b protein, rat
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Animals
• Carotid Artery Injuries (genetics, metabolism, pathology)
• Cell Differentiation
• Cell Movement
• Cell Proliferation
• Cells, Cultured
• Disease Models, Animal
• Extracellular Matrix Proteins (deficiency, genetics, metabolism)
• Gene Expression Regulation
• Genotype
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Muscle, Smooth, Vascular (drug effects, metabolism, pathology)
• Myocytes, Smooth Muscle (drug effects, metabolism, pathology)
• Neointima
• Phenotype
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Rats, Transgenic
• Signal Transduction
• Time Factors