L Koren1, D Alishekevitz2, O Elhanani1, A Nevelsky3, T Hai4, I Kehat5, Y Shaked2, A Aronheim6. 1. Department of Molecular Genetics, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 2. Department of Cell Biology and Cancer Science, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 3. Radiotherapy Department, Rambam Health Care Campus, Haifa, Israel. 4. Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, Ohio USA. 5. Department of Physiology, Biophysics and Systems Biology, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 6. Department of Molecular Genetics, The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Electronic address: aronheim@tx.technion.ac.il.
Abstract
RATIONALE: 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. METHODS AND 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.
RATIONALE: 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. METHODS AND 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: Michael A Burke; Stephen Chang; Hiroko Wakimoto; Joshua M Gorham; David A Conner; Danos C Christodoulou; Michael G Parfenov; Steve R DePalma; Seda Eminaga; Tetsuo Konno; Jonathan G Seidman; Christine E Seidman Journal: JCI Insight Date: 2016-05-05
Authors: Roy Kalfon; Tom Friedman; Shir Eliachar; Rona Shofti; Tali Haas; Lilach Koren; Jacob D Moskovitz; Tsonwin Hai; Ami Aronheim Journal: PLoS One Date: 2019-02-28 Impact factor: 3.240
Authors: Jacqueline Heger; Julia Bornbaum; Alona Würfel; Christian Hill; Nils Brockmann; Renáta Gáspár; János Pálóczi; Zoltán V Varga; Márta Sárközy; Péter Bencsik; Tamás Csont; Szilvia Török; Baktybek Kojonazarov; Ralph Theo Schermuly; Kerstin Böngler; Mariana Parahuleva; Peter Ferdinandy; Rainer Schulz; Gerhild Euler Journal: Sci Rep Date: 2018-05-16 Impact factor: 4.379