Myeloid mineralocorticoid receptor deficiency inhibits aortic constriction-induced cardiac hypertrophy in mice.

Chao Li,Qing Zhen Yang,Ryan A Frieler,Sheng Zhong Duan,Ying Yu,Stefan Berger,Xue Nan Sun,Richard M Mortensen,Wang Wang,Wu Chang Zhang,Yu Yao Zhang,Yong Wu,Baozhuan Huang,Xiao Jun Zheng,Shu Min Ma,Diego Alvarez De La Rosa

doi:10.1371/journal.pone.0110950

Abstract

Mineralocorticoid receptor (MR) blockade has been shown to suppress cardiac hypertrophy and remodeling in animal models of pressure overload (POL). This study aims to determine whether MR deficiency in myeloid cells modulates aortic constriction-induced cardiovascular injuries. Myeloid MR knockout (MMRKO) mice and littermate control mice were subjected to abdominal aortic constriction (AAC) or sham operation. We found that AAC-induced cardiac hypertrophy and fibrosis were significantly attenuated in MMRKO mice. Expression of genes important in generating reactive oxygen species was decreased in MMRKO mice, while that of manganese superoxide dismutase increased. Furthermore, expression of genes important in cardiac metabolism was increased in MMRKO hearts. Macrophage infiltration in the heart was inhibited and expression of inflammatory genes was decreased in MMRKO mice. In addition, aortic fibrosis and inflammation were attenuated in MMRKO mice. Taken together, our data indicated that MR deficiency in myeloid cells effectively attenuated aortic constriction-induced cardiac hypertrophy and fibrosis, as well as aortic fibrosis and inflammation.

Highlights

Chronic inflammation is a major feature of many experimental models of heart failure and hypertrophic remodeling [1]
hematoxylin and eosin (H&E) staining sections were used to measure the cross-sectional area of cardiomyocytes and the results showed that Myeloid MR knockout (MMRKO) mice had smaller cardiomyocytes than littermate control (LC) after abdominal aortic constriction (AAC) (Figure 1B, C)
Pathological cardiac hypertrophy is usually accompanied by a fetal gene program, including increases in ANP, BNP, and bMHC and decrease in PLBN and SERCA2 [17]. qRT-PCR analysis revealed that expression of both ANP and bMHC was significantly suppressed in the ventricular samples from MMRKO compared with LC mice (Figure 1D)

Summary

Introduction

Chronic inflammation is a major feature of many experimental models of heart failure and hypertrophic remodeling [1]. The influence that immune cells and inflammation have on ventricular hypertrophy and remodeling during POL remains underappreciated. Conditional deletion of MR from myeloid cells induced an alternative macrophage phenotype and demonstrated cardiovascular protection in both angiotensin II (Ang-II)/N(G)-nitro-L-arginine methyl ester (LNAME) and uninephrectomy/deoxycorticosterone models [12,13,14]. These data indicate that MR in immune cells, myeloid cells, may play a major role in cardiac hypertrophy and fibrosis after POL

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