AKT-independent activation of p38 MAP kinase promotes vascular calcification

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 revealed association of p38 MAPK with Runx2, which was enhanced by DCA treatment. Knockdown p38 MAPK inhibited DCA-induced Runx2 transactivity, supporting the function of p38 MAPK in regulating Runx2 transactivity.Our studies have uncovered a new function of DCA in regulating vascular calcification, via AKT-independent activation of p38 MAPK. Furthermore, we have identified novel interaction between p38 MAPK and Runx2 enhances Runx2 transactivity, thus promoting VSMC calcification. These results revealed a novel signaling mechanism underlying DCA-induced vascular calcification, and offer opportunities to identify new therapeutic targets.

1,25(OH)2D3regulates the proangiogenic activity of pericyte through VDR‐mediated modulation of VEGF production and signaling of VEGF and PDGF receptors

“…Here, we showed that incubation of PC with 1,25(OH) 2 D 3 activates p38. This is consistent with the reported role of p38 activation in VSMC calcification . However, VEGF, PDGF, or their combination did not activate p38 (Figure A,D).…”

“…The MAPK family of proteins including ERKs and p38, and AKT signaling pathways are involved in regulation of diverse range of cellular processes including 1,25(OH) 2 D 3 ‐mediated VSMC osteoblastic differentiation and calcification . We showed incubation of retinal PC with 1,25(OH) 2 D 3 resulted in p38 and ERK activation.…”

“…The AKT pathway is both proangiogenic and antiangiogenic, and it controls cell survival, cell cycle, cell proliferation, and migration . AKT signaling also plays an important role in VSMC calcification . In retinal PC, 1,25(OH) 2 D 3 decreased AKT activation.…”

“…The family of MAPK and AKT signaling pathways are involved in the regulation of diverse range of cellular processes including 1,25(OH) 2 D 3 mediated VSMC osteoblastic differentiation and calcification . Here, we examined the effect of 1,25(OH) 2 D 3 , VEGF, and VEGF and PDGF on MAPK protein expression and activity including p38 and extracellular‐signal‐regulated kinases (ERK), and AKT in PC (Figure ).…”

Mitochondrial dysfunction generates a growth-restraining signal linked to pyruvate inDrosophilalarvae

“…Pdk knockdown exacerbated the developmental delay of tko 25t (Figure 6(b), ii), but only under conditions of pyruvate overload. Although DCA is a potent inhibitor of Pdk [53], it may also have other targets [54][55][56] and is accumulated in cells via the plasmamembrane monocarboxylate transporters, MCTs [57]. Moreover, in cancer cells, it has been reported to inhibit the pentose phosphate pathway [58] and thereby decrease the level of NADPH, which is already depleted in tko 25t , especially when grown on high-sugar medium [7].…”