Abstract P3016: Pathologic Matrix Markers Are Differentially Modulated By VSMC-Specific SGK-1 Activity In Hypertension And Abdominal Aortic Aneurysm

Abstract

Introduction: The VSMC switch to synthetic phenotype promotes aortic pathology such as hypertension (HTN) and abdominal aortic aneurysm (AAA). Mechanical activation of serum and glucocorticoid inducible kinase-1 (SGK-1) alters the VSMC synthetic profile to promote remodeling. Plasma biomarkers may represent opportunities to assess VSMC function in aortic disease, and we hypothesize that analysis of a panel of plasma pathologic matrix markers (PMM) representing synthetic VSMC phenotype can reflect SGK-1-dependent activity. Methods: HTN was induced in wild-type C57Bl/6 (WT) and smooth muscle cell specific SGK-1 knockout (SMC-SGK-1KO +/- ) mice with AngiotensinII infusion (1.46mg/kg/day, n=4-6). Separate mice underwent AAA induction by peri-adventitial CaCl 2 application (n=4-6). Terminal procedure included collecting systolic blood pressure (SBP), aortic diameter (AoD), and plasma. ELISA for PMMs included Interleukin-6 (IL-6), Matrix Metalloproteinase-9 (MMP-9), Cathepsin S (CtsS), and Cystatin C (CysC), Osteoprotegerin (OPG), and Tenascin C (TNC). Impact of the panel was evaluated by a composite T-score. Statistics included T-test and ANOVA. Results: WT+HTN had >30% increased SBP and elevation of IL-6, CtsS, CysC, and TNC (p<0.05). SMC-SGK-1KO +/- +HTN had equally elevated SBP, but no change in PMMs, suggesting that SGK-1 contributed to HTN-induced VSMC synthetic activity. WT+AAA had >65% increased AoD and elevation of all PMMs (p<0.05). Alternatively, SMC-SGK-1KO +/- +AAA had abrogated growth (29.4 + 3.6%, p<0.05 vs WT and WT+AAA) with IL-6, CtsS, CysC, and TNC returning to baseline, suggesting that SGK-1-dependent production of these PMMS was necessary for true AAA growth. Composite T-scores differed between Control, HTN, and AAA in WT mice (0.78 + 0.08 vs 2.91 + 0.29 vs 7.11 + 0.71 respectively, p<0.05). In SMC-SGK-1KO +/- mice, T-score normalized in HTN but remained elevated in AAA (2.19 + 0.21, p<0.05 vs Control and WT+AAA), attributable to the elevations in MMP-9 and OPG, peptides produced by inflammatory infiltrate. Conclusion: A panel of PMMs can be scored to reflect synthetic activity of VSMCs in aortic pathology, as well as response to inhibition, and warrants further investigation for the clinical care of patients with vascular disease.