Abstract 349: Sgk1 Is a Pivotal Player in Vascular Inflammation and Atherogenesis

Abstract

Objective: Atherosclerosis, an inflammatory disease of arterial vessel wall, requires migration and MMP-9-dependent invasion of macrophages into the vascular wall. MMP-9 expression is stimulated by transcription factor NF-κB, which is regulated by IκB and thus IκB-kinase IKK. Regulators of NF-κB include SGK1. The present study explored involvement of SGK1 in vascular inflammation and atherogenesis. Approach and Results: Gene-targeted ApoE-deficient mice without (apoe-/-sgk1+/+) or with (apoe-/-sgk1-/-) additional SGK1 knockout received 16-weeks cholesterol-rich diet. Atherosclerotic lesions in aorta and carotid artery, vascular CD45+ leukocyte infiltration, Mac-3+ macrophage infiltration, VSMC content, MMP-2 and MMP-9 positive areas in atherosclerotic tissue were significantly less in apoe-/-sgk1-/-mice. Migration of SGK1-deficient CD11b+F4/80+ macrophages was significantly diminished in vitro and in vivo. Zymographic MMP-2 and MMP-9 production, MMP-9 activity and invasion through matrigel in vitro were significantly less in sgk1-/- than in sgk1+/+ macrophages and in control plasmid- or inactive K127NSGK1-transfected than in constitutively active S422DSGK1-transfected THP-1 cells. Plaques of apoe-/-sgk1-/- mice displayed reduced macrophage number and macrophage MMP-9 content. In THP-1 cells MMP-inhibitor GM6001 abrogated S422DSGK1-induced MMP-9 production and invasion. MMP-9 transcript levels were significantly reduced in sgk1-/- macrophages and strongly upregulated in S422DSGK1-transfected THP-1 cells compared to control plasmid- or K127NSGK1-transfected THP-1 cells. Phosphorylation of IKK and IκB and nuclear translocation of p50 were significantly lower in sgk1-/- macrophages than in sgk1+/+ macrophages and significantly higher in S422DSGK1-transfected THP-1 cells than in control plasmid- or K127NSGK1-transfected THP-1 cells. Treatment of S422DSGK1-transfected THP-1 cells with IKK-inhibitor BMS-345541 abolished S422DSGK1-induced increase of MMP-9 transcription and gelatinase activity. Conclusions: SGK1 plays a pivotal role in vascular inflammation during atherogenesis. SGK1 participates in the regulation of macrophage migration and MMP-9 transcription via regulation of NF-κB.