AKT-independent activation of p38 MAP kinase promotes vascular calcification

Redox Biology
Youfeng YangYabing Chen

Abstract

Vascular calcification is prevalent in patients with atherosclerosis, and oxidative stress promotes pathogenesis of atherosclerosis. We have previously reported that activation of AKT by oxidative stress induces vascular calcification. Using sodium dichloroacetate (DCA), a previously reported small molecule inhibitor of AKT, the present studies uncovered an AKT-independent mechanism in regulating vascular calcification. We found that DCA dose-dependently induced calcification of vascular smooth muscle cells (VSMC) in vitro and aortic rings ex vivo. Furthermore, DCA markedly enhanced vascular calcification in atherosclerotic ApoE knockout mice in vivo. DCA-induced VSMC calcification was associated with increased Runx2, but not via activation of AKT, a key upstream signal that upregulates Runx2 during VSMC calcification. In contrast, DCA inhibited AKT activation and induced activation of p38 MAPK in calcified atherosclerotic lesions in vivo and calcified VSMC in vitro. Using a pharmacological inhibitor and shRNA for p38 MAPK, we demonstrated that inhibition of p38 MAPK blocked DCA-induced Runx2 upregulation and VSMC calcification. Furthermore, Runx2 deletion attenuated DCA-induced VSMC calcification. Immunoprecipitation analysis ...Continue Reading

Citations

Apr 3, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Yabing ChenHui Wu
May 15, 2020·Arteriosclerosis, Thrombosis, and Vascular Biology·Melinda DuerCatherine M Shanahan
Dec 12, 2018·Frontiers in Cardiovascular Medicine·Yin TintutLinda L Demer
Mar 20, 2019·Cellular and Molecular Life Sciences : CMLS·Jakob VoelklIoana Alesutan

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Methods Mentioned

BETA
Assay
immunoprecipitation
transfection

Software Mentioned

ImageJ
NIH ImageJ

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