Abstract P300: Cardiac Ly6C high Monocyte Accumulation and Remodeling Depend on the Mineralocorticoid Receptor in Endothelial Cells

Abstract

Introduction: Inflammation is a key driver for the development of cardiac fibrosis and diastolic dysfunction. Aldosterone promotes the expression of adhesion molecules and vascular inflammation. Thus, the goal of the present study was to examine the significance of endothelial MR for pressure overload induced cardiac inflammation and remodeling. Methods and results: Mice with endothelial cell-specific deletion of the mineralocorticoid receptor (MR Cdh5Cre ) were generated using the Cre/loxP system. MR Cdh5Cre and Cre-negative littermates (MR wildtype ) underwent transverse aortic constriction (TAC, n=5-7 per group). After two weeks of pressure overload echocardiography revealed diastolic dysfunction in MR wildtype (mitral valve E acceleration time TAC 15.7 ± 0.5 vs. sham 12.8 ± 0.4 ms, P<0.05) but not in MR Cdh5Cre mice (TAC 11.2 ± 0.6 vs. sham 12.2 ± 0.9 ms, n.s.). Cardiac hypertrophy (ventricle weight 143.2 ± 5.2 vs. MR wildtype 167.3 ± 6.7 mg, P<0.001) and interstitial fibrosis (sirius red stained area 8.2 ± 4.7 vs. MR wildtype 13.5 ± 4.5 %, P<0.05) following TAC were attenuated in MR Cdh5Cre mice. mRNA expression of atrial natriuretic peptide ( Nppa , 2429 ± 1230 vs. MR wildtype 7051 ± 3182 copies/10 4 copies Rps29 , P<0.01) or the fibrosis marker gene collagen 1a1 ( Col1a1 , 256 ± 89 vs. MR wildtype 432 ± 165 copies/10 4 copies Rps29 , P<0.05) as determined by qRT-PCR confirmed these findings. Cardiac leukocytes were quantitatively analyzed by fluorescence assisted cell sorting using specific antibodies. Numbers of CD45 + leukocytes were similarly increased after TAC in the hearts of both genotypes (MR Cdh5Cre 3840 ± 443 vs. MR wildtype 4051 ± 385 /mg tissue, n.s.). Subtype analysis revealed a shift towards CD45 + CD11b + F4/80 low Ly6C high monocytes vs. CD45 + CD11b + F4/80 high Ly6C low macrophages in the heart of MR wildtype (TAC 20 ± 6 vs. sham 4 ± 1 % of CD45 + CD11b + , P<0.05) but not of MR Cdh5Cre mice (TAC 6 ± 2 vs. sham 3 ± 1 % of CD45 + CD11b + , n.s.). Conclusion: MR deletion from endothelial cells ameliorates left ventricular remodeling and diastolic dysfunction after pressure overload. The protective effect of endothelial MR deletion is associated with a shift towards less pro-inflammatory Ly6C high monocytes and more reparative Ly6C low macrophages.