Macrophage Mineralocorticoid Receptor Signaling Plays a Key Role in Aldosterone-Independent Cardiac Fibrosis
Macrophage Mineralocorticoid Receptor Signaling Plays a Key Role in Aldosterone-Independent Cardiac Fibrosis
复制标题
DOI：
10.1210/en.2011-2098
复制
发表时间：
2012-07-01
期刊：
影响因子：
4.8
通讯作者：
Young, Morag J.
中科院分区：
文献类型：
--
作者：
Bienvenu, Laura A.;Morgan, James;Young, Morag J.
盐皮质激素受体（MR）激活促进心脏纤维化和心力衰竭的发展。临床证据表明，即使血浆醛固酮水平没有增加，MR拮抗作用也具有保护作用。我们假设，即使醛固酮水平没有升高，巨噬细胞中的MR激活也会驱动心脏的促纤维化表型。本研究的目的是建立巨噬细胞MR信号在介导一氧化氮（NO）缺乏引起的心脏组织重塑中的作用，这是一种盐皮质激素非依赖性损伤。将雄性野生型（MRflox/flox）和巨噬细胞MR敲除（MRflox/flox/LysMCre/+; mac-MRKO）小鼠单肾切除，维持在0.9%NaCl饮用溶液中，与载体（对照）或一氧化氮合酶（NOS）抑制剂NG-硝基-L-精氨酸甲酯（L-NAME; 150 mg/kg/d）一起8周。与所有其他组相比，野生型L-NAME/盐处理的小鼠在4周时NO缺乏增加收缩压。在第8周，L-NAME/盐处理的野生型和mac-MRKO小鼠的收缩压均高于对照组，L-NAME/盐使其升高约28 mm Hg。在L-NAME/盐处理的野生型和mac-MRKO中，巨噬细胞的募集增加2至3倍。与mac-MRKO相比，野生型L-NAME/盐处理的小鼠中诱导型NOS阳性巨噬细胞浸润和TNF α mRNA表达更高，表明MR丧失降低了M1表型。与对照组相比，野生型和mac-MRKO小鼠中血管炎症和氧化应激标志物（NADPH氧化酶2、p22 phox、细胞间粘附分子-1、G蛋白偶联趋化因子受体5）的mRNA水平相似。相比之下，L-NAME/盐处理增加了野生型小鼠间质胶原沉积约33%，但在mac-MRKO小鼠中没有。在野生型（1.931 +/- 0.215 vs. 1 +/- 0.073）但mac-MRKO小鼠（1.403 +/- 0.150 vs. 1.286 +/- 0.255）中，结缔组织生长因子和胶原蛋白III的mRNA水平也高于对照处理。这些数据表明，巨噬细胞MR是必要的翻译炎症和氧化应激到间质和血管周围纤维化后，NO缺乏，即使血浆醛固酮不升高。（内分泌学153：3416-3425，2012）
Mineralocorticoid receptor (MR) activation promotes the development of cardiac fibrosis and heart failure. Clinical evidence demonstrates that MR antagonism is protective even when plasma aldosterone levels are not increased. We hypothesize that MR activation in macrophages drives the profibrotic phenotype in the heart even when aldosterone levels are not elevated. The aim of the present study was to establish the role of macrophage MR signaling in mediating cardiac tissue remodeling caused by nitric oxide (NO) deficiency, a mineralocorticoid-independent insult. Male wild-type (MRflox/flox) and macrophage MR-knockout (MRflox/flox/LysMCre/+; mac-MRKO) mice were uninephrectomized, maintained on 0.9% NaCl drinking solution, with either vehicle (control) or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (L-NAME; 150 mg/kg/d) for 8 wk. NO deficiency increased systolic blood pressure at 4 wk in wild-type L-NAME/salt-treated mice compared with all other groups. At 8 wk, systolic blood pressure was increased above control in both L-NAME/salt treated wild-type and mac-MRKO mice by approximately 28 mm Hg by L-NAME/salt. Recruitment of macrophages was increased 2- to 3-fold in both L-NAME/salt treated wild-type and mac-MRKO. Inducible NOS positive macrophage infiltration and TNF alpha mRNA expression was greater in wild-type L-NAME/salt-treated mice compared with mac-MRKO, demonstrating that loss of MR reduces M1 phenotype. mRNA levels for markers of vascular inflammation and oxidative stress (NADPH oxidase 2, p22phox, intercellular adhesion molecule-1, G protein-coupled chemokine receptor 5) were similar in treated wild-type and mac-MRKO mice compared with control groups. In contrast, L-NAME/salt treatment increased interstitial collagen deposition in wild-type by about 33% but not in mac-MRKO mice. mRNA levels for connective tissue growth factor and collagen III were also increased above control treatment in wild-type (1.931 +/- 0.215 vs. 1 +/- 0.073) but not mac-MRKO mice (1.403 +/- 0.150 vs. 1.286 +/- 0.255). These data demonstrate that macrophage MR are necessary for the translation of inflammation and oxidative stress into interstitial and perivascular fibrosis after NO deficiency, even when plasma aldosterone is not elevated. (Endocrinology 153: 3416-3425, 2012)