Fluvastatin inhibits advanced glycation end products-induced proliferation, migration, and extracellular matrix accumulation in vascular smooth muscle cells by targeting connective tissue growth factor.
10.4196/kjpp.2018.22.2.193
- Author:
Ae Rang HWANG
1
;
Ju Ock NAM
;
Young Jin KANG
Author Information
1. Department of Pharmacology, College of Medicine, Yeungnam University, Daegu 42415, Korea. yjkang@med.yu.ac.kr
- Publication Type:Original Article
- Keywords:
Advanced glycation end products;
Cell cycle arrest;
Connective tissue growth factor;
Extracellular matrix;
Fluvastatin;
Vascular smooth muscle cell
- MeSH:
Cell Cycle;
Cell Cycle Checkpoints;
Cell Proliferation;
Connective Tissue Growth Factor*;
Connective Tissue*;
Cyclin D1;
Extracellular Matrix*;
Fibrosis;
Genes, Regulator;
Glycosylation End Products, Advanced;
Hydroxymethylglutaryl-CoA Reductase Inhibitors;
Muscle, Smooth, Vascular*;
Phosphotransferases;
RNA, Messenger;
Vascular System Injuries
- From:The Korean Journal of Physiology and Pharmacology
2018;22(2):193-201
- CountryRepublic of Korea
- Language:English
-
Abstract:
Connective tissue growth factor (CTGF) is a novel fibrotic mediator, which is considered to mediate fibrosis through extracellular matrix (ECM) synthesis in diabetic cardiovascular complications. Statins have significant immunomodulatory effects and reduce vascular injury. We therefore examined whether fluvastatin has anti-fibrotic effects in vascular smooth muscle cells (VSMCs) and elucidated its putative transduction signals. We show that advanced glycation end products (AGEs) stimulated CTGF mRNA and protein expression in a time-dependent manner. AGE-induced CTGF expression was mediated via ERK1/2, JNK, and Egr-1 pathways, but not p38; consequently, cell proliferation and migration and ECM accumulation were regulated by CTGF signaling pathway. AGE-stimulated VSMC proliferation, migration, and ECM accumulation were blocked by fluvastatin. However, the inhibitory effect of fluvastatin was restored by administration of CTGF recombinant protein. AGE-induced VSMC proliferation was dependent on cell cycle arrest, thereby increasing G1/G0 phase. Fluvastatin repressed cell cycle regulatory genes cyclin D1 and Cdk4 and augmented cyclin-dependent kinase inhibitors p27 and p21 in AGE-induced VSMCs. Taken together, fluvastatin suppressed AGE-induced VSMC proliferation, migration, and ECM accumulation by targeting CTGF signaling mechanism. These findings might be evidence for CTGF as a potential therapeutic target in diabetic vasculature complication.
