Fluvastatin inhibits advanced glycation end products-induced proliferation, migration, and extracellular matrix accumulation in vascular smooth muscle cells by targeting Connective tissue growth factor

Ae Rang Hwang, Ju Ock Nam, Young Jin Kang

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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. AGEinduced 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.

Original languageEnglish
Pages (from-to)193-201
Number of pages9
JournalKorean Journal of Physiology and Pharmacology
Volume22
Issue number2
DOIs
StatePublished - Mar 2018

Keywords

  • Advanced glycation end products
  • Cell cycle arrest
  • Connective tissue growth factor
  • Extracellular matrix
  • Fluvastatin
  • Vascular smooth muscle cell

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