Fluvastatin inhibits AGE-induced cell proliferation and migration via an ERK5-dependent Nrf2 pathway in vascular smooth muscle cells

• Published in: PloS one Vol. 12; no. 5; p. e0178278
• Main Authors: Hwang, Ae-Rang, Han, Jung-Hwa, Lim, Jae Hyang, Kang, Young Jin, Woo, Chang-Hoon
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.05.2017; Public Library of Science (PLoS)
• Subjects: Advanced glycation end products; Age; Analysis; Animals; Anticholesteremic Agents - pharmacology; Antioxidants; Apoptosis - drug effects; Assaying; Atherosclerosis; Biology and Life Sciences; Cardiovascular system; Cell cycle; Cell growth; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Complications; Complications and side effects; Cyclin D1; Cyclin-dependent kinase 4; Diabetes mellitus; Dosage and administration; Fatty Acids, Monounsaturated - pharmacology; Flow cytometry; Fluvastatin; Gene expression; Gene Expression Regulation - drug effects; Genetic aspects; Glycation End Products, Advanced - pharmacology; Glycosylation; Immunoglobulins; Indoles - pharmacology; Kinases; Medicine; Medicine and Health Sciences; Mitogen-Activated Protein Kinase 7 - genetics; Mitogen-Activated Protein Kinase 7 - metabolism; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; NRF2 protein; Oxidative stress; Oxygen; Pharmacology; Physiological aspects; Pulmonary arteries; Rats; Rats, Sprague-Dawley; Reactive oxygen species; Research and analysis methods; Rodents; siRNA; Smooth muscle; Statins; Vascular diseases; Wounds; South Korea
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0178278

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.