Cardiac macrophages promote diastolic dysfunction.,Journal of Experimental Medicine

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Cardiac macrophages promote diastolic dysfunction.
Journal of Experimental Medicine ( IF 12.6 ) Pub Date : 2018-01-16 , DOI: 10.1084/jem.20171274
Maarten Hulsmans ₁ , Hendrik B Sager ₁ , Jason D Roh _{2,

3} , María Valero-Muñoz ₄ , Nicholas E Houstis _{2,

3} , Yoshiko Iwamoto ₁ , Yuan Sun ₁ , Richard M Wilson ₄ , Gregory Wojtkiewicz ₁ , Benoit Tricot ₁ , Michael T Osborne _{3,

5} , Judy Hung ₃ , Claudio Vinegoni ₁ , Kamila Naxerova _{1,

6} , David E Sosnovik _{2,

3,

5,

7} , Michael R Zile ₈ , Amy D Bradshaw ₈ , Ronglih Liao ₉ , Ahmed Tawakol _{3,

5} , Ralph Weissleder _{1,

10} , Anthony Rosenzweig _{2,

3} , Filip K Swirski ₁ , Flora Sam ₄ , Matthias Nahrendorf _{2,

11}

Affiliation

Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Division of Cardiology and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA.
Cardiac MR PET CT Program, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Gazes Cardiac Research Institute, Medical University of South Carolina, Charleston, SC.
Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Department of Systems Biology, Harvard Medical School, Boston, MA.
Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.

中文翻译：

心脏巨噬细胞促进舒张功能障碍。

巨噬细胞遍布健康的心肌，并且取决于它们的表型，可能会导致组织动态平衡或疾病。尚不清楚它们的起源和在舒张功能障碍中的作用，舒张功能障碍是心脏衰老和心力衰竭且射血分数保持不变的标志。在这里，我们显示心脏巨噬细胞在人和具有舒张功能障碍的小鼠中扩增，这在小鼠中是由高血压或高龄诱导的。单核细胞募集以及骨髓和脾脏中造血功能的增加会导致鼠类心肌巨噬细胞密度更高。在人类中，我们观察到了平行的造血激活星座：循环的髓样细胞更为频繁，脾脏18F-FDG PET / CT成像信号与舒张功能障碍的超声心动图指标相关。当舒张功能障碍发展时，心脏巨噬细胞产生IL-10，激活成纤维细胞并刺激胶原蛋白沉积，从而导致心肌舒张受损和心肌僵硬。巨噬细胞中IL-10的缺失改善了舒张功能。这些数据暗示心脏巨噬细胞的扩张和表型改变是导致心脏舒张功能障碍的心脏纤维化的治疗靶标。

更新日期：2018-02-05

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