Abstract 699: Endothelial Mineralocorticoid Receptor and Neutrophils Mediate Aldo plus Salt-Induced Abdominal Aortic Aneurysm

Abstract

Background: We recently reported that administration of mice with Aldo or deoxycorticosterone acetate (DOCA) plus salt induces abdominal aortic aneurysm (AAA) and treatment of mice with mineralocorticoid receptor (MR) blockers abolished Aldo plus salt-induced AAA. However, the mechanism by which Aldo plus salt induces AAA is largely unknown. Methods: A tamoxifen inducible EC (EC)-specific MR knockout mouse model (iECMRKO) was developed. ECMRKO mice, and control mice were administered with Aldo or DOCA plus sat salt to induce AAA. C57BL/6 mice were injected with anti-mouse polymorphonuclear (PMN) leukocytes antibody to deplete neutrophils. The aortic internal and external diameter, the aortic dilation rate, and the incidence of AAA were determined. Results: Selective genetic deletion of MR from ECs, protects mice from Aldo or DOCA plus salt-induced AAA. EC-specific MR deletion had little effect on Aldo plus salt-induced sodium retention, hypertension, and renal fibrosis, but largely suppressed aortic elastin degradation, matrix metallopeptidase (MMP) 2 and MMP9 upregulation, macrophage and neutrophil infiltration. Surprisingly, neutrophil, but not macrophage, was observed in aorta from control mice, but not iECMRKO mice, indicating that neutrophils but not macrophages is involved in the early processes of Aldo plus salt-induced and endothelia MR-mediated AAA development. Treatment of C57BL/6 mice with of anti- PMN antibody selectively suppressed DOCA plus salt-induced circulating Ly6G-postive neutrophils, but not CD4-postive leukocytes, protected mice from DOCA plus salt-induced AAA. Aldo-induced endothelial adhesion molecule (E-selectin, P-selectin, ICAMP1, and VCAM-1) and proinflammatory cytokine (IL-6 and MCP-1) mRNA expressions were abolished in cultured MR-deficient ECs. Aldo plus salt-induced ICAM-1 but not VCAM-1 protein upregulation was abolished in aorta from ECMRKO mice. Conclusions: Our results demonstrate a significant role of endothelial MR, in Aldo plus salt-induced AAA. Moreover, our results also reveal a provocative mechanism by which ICAM-1, but not VCAM-1, and neutrophils, but not macrophages, mediates the early processes of Aldo plus salt-induced and endothelia MR-mediated AAA development.