Smooth Muscle Cell Specific Activity of SGK-1 Alters Aortic Stiffness and Abdominal Aortic Aneurysm Growth

Background/Objective: Activity of SGK-1 has been associated with mechanical aspects of vascular remodeling and matrix stiffening has been a known characteristic of AAA. We hypothesis that VSMC-specific SGK-1 activity is vital to growth of AAA and contributes to progressive aortic stiffness. Methods: C57Bl/6 and SMC-SGK-1KO+/− mice underwent AAA induction vs Sham on day 0. A subset of C57Bl/6 mice had pump implantation to treat with EMD638683. Aortic ultrasound images were obtained on Day 0 and Day 21 and analyzed for mechanical parameters. At terminal procedure the infrarenal aorta was harvested for immunoblot analysis. Results: At Day 21, C57Bl/6+AAA mice showed growth of 72.27% ± 2.2% versus the C57Bl/6+Sham (p < 0.0001) with associated 3.71 ± 1.15-fold increase in SGK-1 activity (p = 0.001). C57Bl/6+AAA+EMD mice demonstrated growth of 23.68% ± 2.82% (p = 0.0452) with no significant change in SGK-1 activity. SMC-SGK1-KO+/−+AAA mice had growth of 28.20% ± 3.74% compared to SMC-SGK1-KO+/−+Sham (p = 0.004) with increased SGK-1 activity (p = 0.0303). Radial strain was significantly reduced in the C57Bl/6+AAA (p = 0.0062) and C57Bl/6+AAA+EMD (p = 0.0135) when compared to C57Bl/6+Sham. Distensibility was significantly reduced in C57Bl/6+AAA (p = 0.01). Pulse propagation velocity (PPV) was significantly elevated in C57Bl/6+AAA mice (p < 0.0001) but inhibited by EMD therapy (p = 0.0007 vs. C57Bl/6+AAA). SMC-SGK1-KO+/− +AAA mice showed significant reductions in radial strain (p = 0.0011) and distensibility (p = 0.0233) with a modest, but significant, increase in PPV (p = 0.0148). Conclusions: SGK-1 inhibition attenuated AAA growth and preserved vascular function. Targeting this pathway may provide a directed medical therapy for AAA and warrants further investigation.