Rosuvastatin Attenuates CD40L-Induced Downregulation of Extracellular Matrix Production in Human Aortic Smooth Muscle Cells via TRAF6-JNK-NF-κB Pathway.
CD40L and statins exhibit pro-inflammatory and anti-inflammatory effects, respectively. They are both pleiotropic and can regulate extracellular matrix (ECM) degeneration in an atherosclerotic plaque. Statins can decrease both the CD40 expression and the resulting inflammation. However, the effects of CD40L and stains on atherosclerotic plaque ECM production and the underlying mechanisms are not well established. Moreover, prolyl-4-hydroxylase α1 (P4Hα1) is involved in collagen synthesis but its correlations with CD40L and statins are unknown. In the present study, CD40L suppressed P4Hα1 expression in human aortic smooth muscle cells (HASMCs) in a dose- and time-dependent manner, with insignificant changes in MMP2 expression and negative enzymatic activity of MMP9. CD40L increased TRAF6 expression, JNK phosphorylation, NF-κB nuclear translocation as well as DNA binding. Furthermore, silencing TRAF6, JNK or NF-κB genes abolished CD40L-induced suppression of P4Hα1. Lower NF-κB nuclear import rates were observed when JNK or TRAF6 silenced HASMCs were stimulated with CD40L compared to HASMCs with active JNK or TRAF6. Together, these results indicate that CD40L suppresses P4Hα1 expression in HASMCs by activating the TRAF6-JNK- NF-κB pathway. We also found that rosuvastatin inhibits CD40L-induced activation of the TRAF6-JNK- NF-κB pathway, thereby significantly rescuing the CD40L stimulated P4Hα1 inhibition. The results from this study will help find potential targets for stabilizing vulnerable atherosclerotic plaques.
Department of Cardiology, Jinan Central Hospital affiliated to Shandong University, Jinan, Shandong, 250013, P.R. China.
Xiao-Lin
XL
Wang
Department of Health, Jinan Central Hospital affiliated to Shandong University, Jinan, Shandong, 250013, P.R. China.
Yuan-Li
YL
Zhou
Department of Cardiology, Shandong Academy of Medical Sciences, Jinan, Shandong, 250062, P.R. China.
Wei
W
Sun
Department of Cardiology, Jinan Central Hospital affiliated to Shandong University, Jinan, Shandong, 250013, P.R. China.
Li
L
Li
D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D023201:CD40 Ligand / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D000068718:Rosuvastatin Calcium / Q000494:pharmacology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D023201:CD40 Ligand; D000068718:Rosuvastatin Calcium; D048670:MAP Kinase Kinase 4