1. Fluvastatin inhibits AGE-induced cell proliferation and migration via anERK5-dependent Nrf2 pathway in vascular smooth muscle cells
- Author
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Chang Hoon Woo, Jung Hwa Han, Jae Hyang Lim, Youngjin Kang, and Ae Rang Hwang
- Subjects
Glycation End Products, Advanced ,0301 basic medicine ,Indoles ,Vascular smooth muscle ,Cell ,lcsh:Medicine ,Apoptosis ,Biochemistry ,Antioxidants ,Muscle, Smooth, Vascular ,Fatty Acids, Monounsaturated ,Rats, Sprague-Dawley ,0302 clinical medicine ,Cell Movement ,Medicine and Health Sciences ,Enzyme assays ,Small interfering RNAs ,Cell Cycle and Cell Division ,Colorimetric assays ,lcsh:Science ,Bioassays and physiological analysis ,Cells, Cultured ,MTT assay ,Multidisciplinary ,Anticholesteremic Agents ,Drugs ,Cell cycle ,Cell biology ,Nucleic acids ,medicine.anatomical_structure ,Cell Processes ,030220 oncology & carcinogenesis ,Research Article ,medicine.drug ,NF-E2-Related Factor 2 ,Biology ,03 medical and health sciences ,Cyclin D1 ,Downregulation and upregulation ,Cyclins ,Genetics ,medicine ,Animals ,Non-coding RNA ,Fluvastatin ,Cell Cycle Inhibitors ,Mitogen-Activated Protein Kinase 7 ,Cell Proliferation ,Pharmacology ,Cell growth ,lcsh:R ,Statins ,Biology and Life Sciences ,Cell Biology ,Gene regulation ,Rats ,Research and analysis methods ,030104 developmental biology ,Gene Expression Regulation ,Biochemical analysis ,RNA ,lcsh:Q ,Gene expression - Abstract
Advanced glycation endproduct (AGE)-induced vascular smooth muscle cell (VSMC) proliferation and reactive oxygen species (ROS) production are emerging as important mechanisms of diabetic vasculopathy, but little is known about the molecular mechanism responsible for the antioxidative effects of statins on AGEs. It has been reported that statins exert pleiotropic effects on the cardiovascular system due to decreases in AGE-induced cell proliferation, migration, and vascular inflammation. Thus, in the present study, the authors investigated the molecular mechanism by which statins decrease AGE-induced cell proliferation and VSMC migration. In cultured VSMCs, statins upregulated Nrf2-related antioxidant gene, NQO1 and HO-1, via an ERK5-dependent Nrf2 pathway. Inhibition of ERK5 by siRNA or BIX02189 (a specific ERK5 inhibitor) reduced the statin-induced upregulations of Nrf2, NQO1, and HO-1. Furthermore, fluvastatin was found to significantly increase ARE promoter activity through ERK5 signaling, and to inhibit AGE-induced VSMC proliferation and migration as determined by MTT assay, cell counting, FACS analysis, a wound scratch assay, and a migration chamber assay. In addition, AGE-induced proliferation was diminished in the presence of Ad-CA-MEK5α encoding a constitutively active mutant form of MEK5α (an upstream kinase of ERK5), whereas depletion of Nrf2 restored statin-mediated reduction of AGE-induced cell proliferation. Moreover, fluvastatin suppressed the protein expressions of cyclin D1 and Cdk4, but induced p27, and blocked VSMC proliferation by regulating cell cycle. These results suggest statin-induced activation of an ERK5-dependent Nrf2 pathway reduces VSMC proliferation and migration induced by AGEs, and that the ERK5-Nrf2 signal module be viewed as a potential therapeutic target of vasculopathy in patients with diabetes and complications of the disease.
- Published
- 2017