Rationale:The initial hypertrophy response to cardiac pressure overload is considered compensatory, but with sustained stress, it eventually leads to heart failure. Recently, a role for recruited macrophages in determining the transition from compensated to decompensated hypertrophy has been established. However, whether cardiac resident immune cells influence the early phase of hypertrophy development has not been established.Objective:To assess the role of cardiac immune cells in the early hypertrophy response to cardiac pressure overload induced by transverse aortic constriction (TAC).Methods and Results:We performed cytometry by time-of-flight to determine the identity and abundance of immune cells in the heart at 1 and 4 weeks after TAC. We observed a substantial increase in cardiac macrophages 1 week after TAC. We then conducted Cite-Seq single-cell RNA sequencing of cardiac immune cells isolated from 4 sham and 6 TAC hearts. We identified 12 clusters of monocytes and macrophages, categorized as either resident or recruited macrophages, that showed remarkable changes in their abundance between sham and TAC conditions. To determine the role of cardiac resident macrophages early in the response to a hypertrophic stimulus, we used a blocking antibody against macrophage colony-stimulating factor 1 receptor (CD115). As blocking CD115 initially depletes all macrophages, we allowed the replenishment of recruited macrophages by monocytes before performing TAC. This preferential depletion of resident macrophages resulted in enhanced fibrosis and a blunted angiogenesis response to TAC. Macrophage depletion in CCR2 (C-C chemokine receptor type 2) knockout mice showed that aggravated fibrosis was primarily caused by the recruitment of monocyte-derived macrophages. Finally, 6 weeks after TAC these early events lead to depressed cardiac function and enhanced fibrosis, despite complete restoration of cardiac immune cells.Conclusions:Cardiac resident macrophages are a heterogeneous population of immune cells with key roles in stimulating angiogenesis and inhibiting fibrosis in response to cardiac pressure overload.

中文翻译：

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心脏常驻巨噬细胞预防纤维化并刺激血管生成

理由：对心脏压力超负荷的初始肥大反应被认为是补偿性的，但随着持续的压力，它最终会导致心力衰竭。最近，已确定募集的巨噬细胞在确定从代偿性肥大到失代偿性肥大的转变中的作用。然而，心脏常驻免疫细胞是否会影响肥大发育的早期阶段尚未确定。目的：评估心脏免疫细胞在横断主动脉缩窄（TAC）引起的心脏压力超负荷的早期肥大反应中的作用。方法和结果：我们通过飞行时间进行细胞计数，以确定 TAC 后 1 周和 4 周时心脏中免疫细胞的特性和丰度。我们观察到 TAC 后 1 周心脏巨噬细胞显着增加。然后，我们对从 4 个假心脏和 6 个 TAC 心脏中分离的心脏免疫细胞进行了 Cite-Seq 单细胞 RNA 测序。我们确定了 12 个单核细胞和巨噬细胞簇，分类为驻留或募集的巨噬细胞，它们在假和 TAC 条件下的丰度显示出显着变化。为了确定心脏驻留巨噬细胞在对肥大刺激的早期反应中的作用，我们使用了一种针对巨噬细胞集落刺激因子 1 受体 (CD115) 的阻断抗体。由于阻断 CD115 最初会耗尽所有巨噬细胞，我们允许在执行 TAC 之前通过单核细胞补充募集的巨噬细胞。这种对常驻巨噬细胞的优先消耗导致纤维化增强和对 TAC 的血管生成反应减弱。CCR2（CC 趋化因子受体 2 型）敲除小鼠中的巨噬细胞耗竭表明，纤维化加重主要是由单核细胞来源的巨噬细胞募集引起的。最后，在 TAC 后 6 周，尽管心脏免疫细胞完全恢复，但这些早期事件导致心脏功能下降和纤维化增强。结论：心脏常驻巨噬细胞是一种异质的免疫细胞群，在刺激血管生成和抑制纤维化方面具有关键作用。心脏压力超负荷。