Koren L, Alishekevitz D, Elhanani O, Nevelsky A, Hai T, Kehat I, Shaked Y, Aronheim A
Department of Molecular Genetics, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Department of Cell Biology and Cancer Science, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Int J Cardiol. 2015 Nov 1;198:232-40. doi: 10.1016/j.ijcard.2015.06.099. Epub 2015 Jul 9.
Pressure overload induces adaptive remodeling processes in the heart. However, when pressure overload persists, adaptive changes turn into maladaptive alterations leading to cardiac hypertrophy and heart failure. ATF3 is a stress inducible transcription factor that is transiently expressed following neuroendocrine stimulation. However, its role in chronic pressure overload dependent cardiac hypertrophy is currently unknown.
The objective of the study was to study the role of ATF3 in chronic pressure overload dependent cardiac remodeling processes.
Pressure overload was induced by phenylephrine (PE) mini-osmotic pumps in various mice models of whole body, cardiac specific, bone marrow (BM) specific and macrophage specific ATF3 ablations. We show that ATF3-KO mice exhibit a significantly reduced expression of cardiac remodeling markers following chronic pressure overload. Consistently, the lack of ATF3 specifically in either cardiomyocytes or BM derived cells blunts the hypertrophic response to PE infusion. A unique cross-talk between cardiomyocytes and macrophages was identified. Cardiomyocytes induce an ATF3 dependent induction of an inflammatory response leading to macrophage recruitment to the heart. Adoptive transfer of wild type macrophages, but not ATF3-KO derived macrophages, into wild type mice potentiates maladaptive response to PE infusion.
Collectively, this study places ATF3 as a key regulator in promoting pressure overload induced cardiac hypertrophy through a cross-talk between cardiomyocytes and macrophages. Inhibiting this cross-talk may serve as a useful approach to blunt maladaptive remodeling processes in the heart.
压力超负荷会诱导心脏发生适应性重塑过程。然而，当压力超负荷持续存在时，适应性变化会转变为适应不良的改变，导致心脏肥大和心力衰竭。ATF3是一种应激诱导转录因子，在神经内分泌刺激后短暂表达。然而，其在慢性压力超负荷依赖性心脏肥大中的作用目前尚不清楚。
本研究旨在探讨ATF3在慢性压力超负荷依赖性心脏重塑过程中的作用。
在全身、心脏特异性、骨髓（BM）特异性和巨噬细胞特异性ATF3基因敲除的各种小鼠模型中，通过苯肾上腺素（PE）微型渗透泵诱导压力超负荷。我们发现，慢性压力超负荷后，ATF3基因敲除小鼠心脏重塑标志物的表达显著降低。同样，仅在心肌细胞或BM衍生细胞中缺乏ATF3会减弱对PE输注的肥大反应。我们还发现了心肌细胞与巨噬细胞之间独特的相互作用。心肌细胞诱导ATF3依赖性炎症反应，导致巨噬细胞募集到心脏。将野生型巨噬细胞而非ATF3基因敲除小鼠来源的巨噬细胞过继转移到野生型小鼠中，会增强对PE输注的适应不良反应。
总体而言，本研究表明ATF3通过心肌细胞与巨噬细胞之间的相互作用，在促进压力超负荷诱导的心脏肥大中起关键调节作用。抑制这种相互作用可能是减轻心脏适应不良重塑过程的有效方法。
