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.