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Adenosine monophosphate-activated protein kinase-?2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation.

ABSTRACT: OBJECTIVE:Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical events in the progression of several vasculopathologies. Adenosine monophosphate-activated protein kinase (AMPK) has been shown to play a pivotal role in cellular proliferation and migration. However, the roles of AMPK in VSMC migration and its underlying molecular mechanisms remain elusive. APPROACH AND RESULTS:VSMC migration and the neointima formation were studied in cultured mouse VSMCs or in carotid artery ligation of wild-type C57BL/6J mice, AMPK?2, AMPK?1 homozygous-deficient (AMPK?2(-/-), AMPK?1(-/-)) mice. Deletion of AMPK?2, but not AMPK?1, led to increased phosphorylation of both I?B kinase ? and its downstream target nuclear factor ?B2/p100 at serine 866/870. Consequently, phosphor-p100 at S866/870 bound with E3 ubiquitin ligase ?-transducin repeat-containing protein resulting in the proteolytic processing of the p100 precursor and nuclear factor ?B2/p52 induction. Interestingly, acetylation of histone H3 at lysine 56 mediated by histone deacetylase-3 reduction was enhanced significantly in AMPK?2(-/-) VSMCs compared with wild-type or AMPK?1(-/-) VSMCs. Moreover, the augmented association of p52/acetylation of histone H3 at lysine 56 with the promoter of ubiquitin E3 ligase, S-phase kinase-associated protein 2, was shown in AMPK?2(-/-) VSMCs by chromatin immunoprecipitation assay. Furthermore, AMPK?2 deletion caused S-phase kinase-associated protein 2-mediated E-cadherin downregulation. S-Phase kinase-associated protein 2 siRNA abolished the increased migration of AMPK?2(-/-) VSMCs via E-cadherin upregulation. Finally, neointima formation after ligation of carotid artery was increased in AMPK?2(-/-), but not AMPK?1(-/-), mice. CONCLUSIONS:We conclude that deletion of AMPK?2 causes aberrant VSMC migration with accelerated neointima formation in vivo.

SUBMITTER: Song P

PROVIDER: S-EPMC3910301 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Adenosine monophosphate-activated protein kinase-α2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation.

Song Ping P Zhou Yanhong Y Coughlan Kathleen A KA Dai Xiaoyan X Xu Hairong H Viollet Benoit B Zou Ming-Hui MH

Arteriosclerosis, thrombosis, and vascular biology 20131010 12

<h4>Objective</h4>Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) are critical events in the progression of several vasculopathologies. Adenosine monophosphate-activated protein kinase (AMPK) has been shown to play a pivotal role in cellular proliferation and migration. However, the roles of AMPK in VSMC migration and its underlying molecular mechanisms remain elusive.<h4>Approach and results</h4>VSMC migration and the neointima formation were studied in cultured mou ...[more]

PMID: 24115035

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Project description:Background and objectivesResolvin D1 (RvD1) is a specialized pro-resolving lipid mediator that has been previously shown to attenuate vascular smooth muscle cell (VSMC) migration, a key process in the development of intimal hyperplasia. We sought to investigate the role of the cAMP/PKA pathway in mediating the effects of the aspirin-triggered epimer 17R-RvD1 (AT-RvD1) on VSMC migration.MethodsVSMCs were harvested from human saphenous veins. VSMCs were analyzed for intracellular cAMP levels and PKA activity after exposure to AT-RvD1. Platelet-derived growth factor (PDGF)-induced migration and cytoskeletal changes in VSMCs were observed through scratch, Transwell, and cell shape assays in the presence or absence of a PKA inhibitor (Rp-8-Br-cAMP). Further investigation of the pathways involved in AT-RvD1 signaling was performed by measuring Rac1 activity, vasodilator stimulated phosphoprotein (VASP) phosphorylation and paxillin translocation. Finally, we examined the role of RvD1 receptors (GPR32 and ALX/FPR2) in AT-RvD1 induced effects on VSMC migration and PKA activity.ResultsTreatment with AT-RvD1 induced a significant increase in cAMP levels and PKA activity in VSMCs at 5 minutes and 30 minutes, respectively. AT-RvD1 attenuated PDGF-induced VSMC migration and cytoskeletal rearrangements. These effects were attenuated by the PKA inhibitor Rp-8-Br-cAMP, suggesting cAMP/PKA involvement. Treatment of VSMC with AT-RvD1 inhibited PDGF-stimulated Rac1 activity, increased VASP phosphorylation, and attenuated paxillin localization to focal adhesions; these effects were negated by the addition of Rp-8-Br-cAMP. The effects of AT-RvD1 on VSMC migration and PKA activity were attenuated by blocking ALX/FPR2, suggesting an important role of this G-protein coupled receptor.ConclusionsOur results suggest that AT-RvD1 attenuates PDGF-induced VSMC migration via ALX/FPR2 and cAMP/PKA. Interference with Rac1, VASP and paxillin function appear to mediate the downstream effects of AT-RvD1 on VSMC migration.

Dataset Information

Adenosine monophosphate-activated protein kinase-?2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation.

Publications

Adenosine monophosphate-activated protein kinase-α2 deficiency promotes vascular smooth muscle cell migration via S-phase kinase-associated protein 2 upregulation and E-cadherin downregulation.

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