Roy Kalfon1, Lilach Koren1, Sharon Aviram1, Ortal Schwartz2, Tsonwin Hai3, Ami Aronheim4. 1. Department of Cell Biology and Cancer Science, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 7th Efron St., Bat-Galim, Haifa 31096, Israel. 2. Biomedical Core Facility, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 3. Departments of Biological Chemistry and Pharmacology, Ohio State University, 1060 Carmack road, Columbus, OH 43210, USA. 4. Department of Cell Biology and Cancer Science, B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, 7th Efron St., Bat-Galim, Haifa 31096, Israel; aronheim@tx.technion.ac.il.
Abstract
AIMS: Obesity and type 2 diabetes (T2D) trigger a harmful stress-induced cardiac remodeling process known as cardiomyopathy. These diseases represent a serious and widespread health problem in the Western world; however the underlying molecular basis is not clear. ATF3 is an 'immediate early' gene whose expression is highly and transiently induced in response to multiple stressors such as metabolic, oxidative, endoplasmic reticulum and inflammation, stressors that are involved in T2D cardiomyopathy. The role of ATF3 in diabetic cardiomyopathy is currently unknown. Our research has aimed to study the effect of ATF3 expression on cardiomyocytes, heart function and glucose homeostasis in an obesity-induced T2D mouse model. METHODS AND RESULTS: We used wild type mice (WT) as well as mutant mice with a cardiac-specific ATF3 deficiency (ATF3-cKO). Mice were fed a high-fat diet (HFD) for 15 weeks. HFD induced high ATF3 expression in cardiomyocytes. Mice were examined for cardiac remodeling processes and the diabetic state was assessed. HFD-fed ATF3-cKO mice exhibited severe cardiac fibrosis, higher levels of heart hypertrophic markers, increased inflammation and worse cardiac function, as compared to WT mice. Interestingly, HFD-fed ATF3-cKO mice display increased hyperglycemia and reduced glucose tolerance, despite higher blood insulin levels, as compared to HFD-fed WT mice. Elevated levels of the cardiac inflammatory cytokines IL-6 and TNFα leading to impaired insulin signalling may partially explain the peripheral glucose intolerance. CONCLUSIONS: Cardiac ATF3 has a protective role in dampening the HFD-induced cardiac remodeling processes. ATF3 exerts both local and systemic effects related to T2D-induced cardiomyopathy. This study provides a strong relationship between heart remodeling processes and blood glucose homeostasis. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Obesity and type 2 diabetes (T2D) trigger a harmful stress-induced cardiac remodeling process known as cardiomyopathy. These diseases represent a serious and widespread health problem in the Western world; however the underlying molecular basis is not clear. ATF3 is an 'immediate early' gene whose expression is highly and transiently induced in response to multiple stressors such as metabolic, oxidative, endoplasmic reticulum and inflammation, stressors that are involved in T2D cardiomyopathy. The role of ATF3 in diabetic cardiomyopathy is currently unknown. Our research has aimed to study the effect of ATF3 expression on cardiomyocytes, heart function and glucose homeostasis in an obesity-induced T2D mouse model. METHODS AND RESULTS: We used wild type mice (WT) as well as mutant mice with a cardiac-specific ATF3 deficiency (ATF3-cKO). Mice were fed a high-fat diet (HFD) for 15 weeks. HFD induced high ATF3 expression in cardiomyocytes. Mice were examined for cardiac remodeling processes and the diabetic state was assessed. HFD-fed ATF3-cKO mice exhibited severe cardiac fibrosis, higher levels of heart hypertrophic markers, increased inflammation and worse cardiac function, as compared to WT mice. Interestingly, HFD-fed ATF3-cKO mice display increased hyperglycemia and reduced glucose tolerance, despite higher blood insulin levels, as compared to HFD-fed WT mice. Elevated levels of the cardiac inflammatory cytokines IL-6 and TNFα leading to impaired insulin signalling may partially explain the peripheral glucose intolerance. CONCLUSIONS: Cardiac ATF3 has a protective role in dampening the HFD-induced cardiac remodeling processes. ATF3 exerts both local and systemic effects related to T2D-induced cardiomyopathy. This study provides a strong relationship between heart remodeling processes and blood glucose homeostasis. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Tanner O Monroe; Matthew C Hill; Yuka Morikawa; John P Leach; Todd Heallen; Shuyi Cao; Peter H L Krijger; Wouter de Laat; Xander H T Wehrens; George G Rodney; James F Martin Journal: Dev Cell Date: 2019-02-14 Impact factor: 12.270
Authors: Jinliang Li; Yuliang Tan; Catherine L Passariello; Eliana C Martinez; Michael D Kritzer; Xueyi Li; Xiaofeng Li; Yang Li; Qian Yu; Kenneth Ohgi; Hrishikesh Thakur; John W MacArthur; Jan R Ivey; Y Joseph Woo; Craig A Emter; Kimberly Dodge-Kafka; Michael G Rosenfeld; Michael S Kapiloff Journal: Circulation Date: 2020-09-16 Impact factor: 29.690
Authors: Jayasimman Rajendran; Janne Purhonen; Saara Tegelberg; Olli-Pekka Smolander; Matthias Mörgelin; Jan Rozman; Valerie Gailus-Durner; Helmut Fuchs; Martin Hrabe de Angelis; Petri Auvinen; Eero Mervaala; Howard T Jacobs; Marten Szibor; Vineta Fellman; Jukka Kallijärvi Journal: EMBO Mol Med Date: 2019-01 Impact factor: 12.137