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Atorvastatin attenuates homocysteine-induced migration of smooth muscle cells through mevalonate pathway involving reactive oxygen species and p38 MAPK.
Clin Exp Pharmacol Physiol. 2015 Aug; 42(8):865-73.CE

Abstract

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 (VSMCs) induced by Hcy. In this study, it was investigated whether and how atorvastatin could inhibit the Hcy-induced migration in cultured VSMCs and revealed the possible redox mechanism. VSMCs were isolated from the thoracic aortas of Sprague-Dawley rats. The migration of VSMCs 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-p38MAPK 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 VSMCs 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 SB203580 blocked Hcy-induced VSMCs migration. Furthermore, atorvastatin suppressed Hcy-induced activation of NADPH oxidase and ROS, attenuated Hcy-induced overexpression of Nox1mRNA. Similar effects occurred with VSMCs transfected with Nox1 siRNA. Moreover, atorvastatin other than DPI, NAC, SB203580 and Nox1 siRNA 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.

Authors+Show Affiliations

Department of Cardiology, Xuhui District Central Hospital, Shanghai, China.Department of Cardiology, Xuhui District Central Hospital, Shanghai, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26041506

Citation

Bao, Xiao-mei, and Hongchao Zheng. "Atorvastatin Attenuates Homocysteine-induced Migration of Smooth Muscle Cells Through Mevalonate Pathway Involving Reactive Oxygen Species and P38 MAPK." Clinical and Experimental Pharmacology & Physiology, vol. 42, no. 8, 2015, pp. 865-73.
Bao XM, Zheng H. Atorvastatin attenuates homocysteine-induced migration of smooth muscle cells through mevalonate pathway involving reactive oxygen species and p38 MAPK. Clin Exp Pharmacol Physiol. 2015;42(8):865-73.
Bao, X. M., & Zheng, H. (2015). Atorvastatin attenuates homocysteine-induced migration of smooth muscle cells through mevalonate pathway involving reactive oxygen species and p38 MAPK. Clinical and Experimental Pharmacology & Physiology, 42(8), 865-73. https://doi.org/10.1111/1440-1681.12435
Bao XM, Zheng H. Atorvastatin Attenuates Homocysteine-induced Migration of Smooth Muscle Cells Through Mevalonate Pathway Involving Reactive Oxygen Species and P38 MAPK. Clin Exp Pharmacol Physiol. 2015;42(8):865-73. PubMed PMID: 26041506.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Atorvastatin attenuates homocysteine-induced migration of smooth muscle cells through mevalonate pathway involving reactive oxygen species and p38 MAPK. AU - Bao,Xiao-mei, AU - Zheng,Hongchao, PY - 2014/11/13/received PY - 2015/05/04/revised PY - 2015/05/27/accepted PY - 2015/6/5/entrez PY - 2015/6/5/pubmed PY - 2016/5/18/medline KW - atorvastatin KW - homocysteine KW - migration KW - p38 MAPK KW - reactive oxygen species SP - 865 EP - 73 JF - Clinical and experimental pharmacology & physiology JO - Clin. Exp. Pharmacol. Physiol. VL - 42 IS - 8 N2 - 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 (VSMCs) induced by Hcy. In this study, it was investigated whether and how atorvastatin could inhibit the Hcy-induced migration in cultured VSMCs and revealed the possible redox mechanism. VSMCs were isolated from the thoracic aortas of Sprague-Dawley rats. The migration of VSMCs 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-p38MAPK 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 VSMCs 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 SB203580 blocked Hcy-induced VSMCs migration. Furthermore, atorvastatin suppressed Hcy-induced activation of NADPH oxidase and ROS, attenuated Hcy-induced overexpression of Nox1mRNA. Similar effects occurred with VSMCs transfected with Nox1 siRNA. Moreover, atorvastatin other than DPI, NAC, SB203580 and Nox1 siRNA 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. SN - 1440-1681 UR - https://www.unboundmedicine.com/medline/citation/26041506/Atorvastatin_attenuates_homocysteine_induced_migration_of_smooth_muscle_cells_through_mevalonate_pathway_involving_reactive_oxygen_species_and_p38_MAPK_ L2 - https://doi.org/10.1111/1440-1681.12435 DB - PRIME DP - Unbound Medicine ER -