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2018 ; 22
(2
): 193-201
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gab.com Text
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Fluvastatin inhibits advanced glycation end products-induced proliferation,
migration, and extracellular matrix accumulation in vascular smooth muscle cells
by targeting connective tissue growth factor
#MMPMID29520172
Hwang AR
; Nam JO
; Kang YJ
Korean J Physiol Pharmacol
2018[Mar]; 22
(2
): 193-201
PMID29520172
show ga
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.