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Atorvastatin attenuates homocysteine‐induced migration of smooth muscle cells through mevalonate pathway involving reactive oxygen species and p38 MAPK
Author(s) -
Bao Xiaomei,
Zheng Hongchao
Publication year - 2015
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.12435
Subject(s) - nox1 , nadph oxidase , atorvastatin , vascular smooth muscle , reactive oxygen species , chemistry , nox4 , p38 mitogen activated protein kinases , western blot , mevalonate pathway , biochemistry , mapk/erk pathway , microbiology and biotechnology , pharmacology , signal transduction , endocrinology , biology , enzyme , reductase , smooth muscle , gene
Summary Statins have been reported to have an antioxidant effect against homocysteine (Hcy)‐induced endothelial dysfunction. It is unknown whether they have the same effect against migration of vascular smooth muscle cells ( VSMC s) induced by Hcy. In this study, it was investigated whether and how atorvastatin could inhibit the Hcy‐induced migration in cultured VSMC s and revealed the possible redox mechanism. VSMC s were isolated from the thoracic aortas of Sprague‐Dawley rats. The migration of VSMC s was examined using a transwell technique and cell viability was determined by 3‐(4, 5‐dimethylthiazol‐2‐yl)‐2, 5‐diphenyltetrazoliumbromide ( MTT ) assay. Reactive oxygen species ( ROS ) were measured using the fluoroprobe 2′7′‐dichlorodihydrofluorescein diacetate. The activity of NADPH oxidase was assessed by lucigenin enhanced chemiluminescence. Expressions of Nox1 mRNA and p‐p38 MAPK protein were measured by reverse transcription–polymerase chain reaction ( RT – PCR ) and Western blot analysis, respectively. The results showed that atorvastatin inhibited the migration of VSMC s induced by Hcy, which was reversed by the mevalonate. In addition, pretreatment with the NADPH oxidase inhibitor DPI , the free radical scavenger NAC and the p38 MAPK inhibitor SB 203580 blocked Hcy‐induced VSMC s migration. Furthermore, atorvastatin suppressed Hcy‐induced activation of NADPH oxidase and ROS , attenuated Hcy‐induced overexpression of Nox1m RNA . Similar effects occurred with VSMC s transfected with Nox1 si RNA . Moreover, atorvastatin other than DPI , NAC , SB 203580 and Nox1 si RNA transfection blocked Hcy‐induced p38 MAPK phosphorylation, which was also reversed by the mevalonate. The data demonstrates that atorvastatin inhibits Hcy‐induced VSMCs migration in a mevalonate pathway. Furthermore, a part of the biological effect of atorvastatin involves a decrease in the levels of Nox1‐dependent ROS generation and p38 MAPK activation.