title: ATF3-dependent cross-talk between cardiomyocytes and macrophages promotes cardiac maladaptive remodeling.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  The objective of the study was to study the role of ATF3 in chronic pressure overload dependent cardiac remodeling processes.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Molecular Genetics, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: L
authors.initials: L
authors.lastname: Koren
authors.affiliation: Department of Cell Biology and Cancer Science, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Alishekevitz
authors.affiliation: Department of Molecular Genetics, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: O
authors.initials: O
authors.lastname: Elhanani
authors.affiliation: Radiotherapy Department, Rambam Health Care Campus, Haifa, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Nevelsky
authors.affiliation: Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, Ohio USA.
authors.forename: T
authors.initials: T
authors.lastname: Hai
authors.affiliation: Department of Physiology, Biophysics and Systems Biology, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Kehat
authors.affiliation: Department of Cell Biology and Cancer Science, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Y
authors.initials: Y
authors.lastname: Shaked
authors.affiliation: Department of Molecular Genetics, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: aronheim@tx.technion.ac.il.
authors.forename: A
authors.initials: A
authors.lastname: Aronheim
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis / Q000172:deficiency*; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse
keywords: Bone marrow transplantation; Cardiac hypertrophy; Cardiac remodeling; Macrophages; Pressure overload