2017 Cardiovascular Research Day Abstract Book
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34<br />
Endothelial Mineralocorticoid Receptor and Neutrophils Mediate Aldo plus Salt-Induced<br />
Abdominal Aortic Aneurysm<br />
Shu Liu 1 • Yu Zhong 1 • Zhenheng Guo 2 • Ming Gong 1<br />
1Physiology, University of Kentucky • 2 Pharmacology and Nutritional Sciences, University of<br />
Kentucky<br />
Staff<br />
<strong>Abstract</strong><br />
Objective—We recently reported that administration of mice with aldosterone (Aldo) or<br />
deoxycorticosterone acetate (DOCA) plus salt induces AAA via mineralocorticoid receptor (MR).<br />
The current study defines the specific roles of endothelial and myeloid cell MR in DOCA-salt<br />
induced AAA.<br />
Approach and Results—A tamoxifen inducible endothelial cell (EC)-specific MR knockout mouse<br />
model (iECMRKO) and a myeloid cell-specific MR knockout mouse model (MyMRKO) were<br />
developed. The iECMRKO mice, but not the MyMRKO mice were protected from Aldo- or DOCA-saltinduced<br />
AAA. Mechanistically, EC-specific MR deletion had little effect on Aldo-salt-induced salt<br />
retention, hypertension, and renal fibrosis, but largely suppressed aortic elastin degradation,<br />
matrix metalloproteinase-2 (MMP-2) and MMP-9 upregulation, macrophage and neutrophil<br />
infiltration. Surprisingly, neutrophils, but not macrophages, were observed in the aorta 1 week<br />
after Aldo-salt administration in control mice, but not in iECMRKO mice. Treatment of C57BL/6<br />
mice with an anti-PMN antibody selectively suppressed Aldo-salt-induced circulating Ly6G-postive<br />
neutrophils, but not CD4-postive leukocytes, and protected mice from Aldo-salt-induced AAA. In<br />
cell cultures, Aldo-induced endothelial adhesion molecules (E-selectin, P-selectin, and ICAM-1, but<br />
not VCAM-1) and proinflammatory cytokine (IL-6 and MCP-1) mRNA expressions were abolished in<br />
MR-deficient ECs. Importantly, Aldo-salt-induced ICAM-1 but not VCAM-1 protein upregulation was<br />
abolished in aortas from iECMRKO mice.<br />
Conclusions—Endothelial MR, but not myeloid cell MR, plays an important role in Aldo-salt-induced<br />
AAA. Moreover, ICAM-1, but not VCAM-1; and neutrophils, but not macrophages, mediate the early<br />
processes of Aldo-salt-induced and endothelial MR-mediated AAA development.<br />
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