An Update on the Multifaceted Roles of STAT3 in the Heart Zeina Harhous, George Booz, Michel Ovize, Gabriel Bidaux, Mazen Kurdi To cite this version: Zeina Harhous, George Booz, Michel Ovize, Gabriel Bidaux, Mazen Kurdi. An Update on the Multi- faceted Roles of STAT3 in the Heart. Frontiers in Cardiovascular Medicine, Frontiers Media, 2019, 6, 10.3389/fcvm.2019.00150. hal-03060373 HAL Id: hal-03060373 https://hal.archives-ouvertes.fr/hal-03060373 Submitted on 13 Dec 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. 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REVIEW published: 25 October 2019 doi: 10.3389/fcvm.2019.00150 An Update on the Multifaceted Roles of STAT3 in the Heart Zeina Harhous 1,2,3,GeorgeW.Booz4,MichelOvize2,3,GabrielBidaux2,3* and Mazen Kurdi 1* 1 Laboratory of Experimental and Clinical Pharmacology, Faculty of Sciences, Doctoral School of Sciences and Technology, Lebanese University, Beirut, Lebanon, 2 Univ-Lyon, CarMeN Laboratory, INSERM 1060, INRA 1397, University Claude Bernard Lyon1, INSA Lyon, Oullins, France, 3 IHU OPeRa, Groupement Hospitalier EST, Bron, France, 4 Department of Pharmacology and Toxicology, School of Medicine, The University of Mississippi Medical Center, Jackson, MS, United States Signal transducer and activator of transcription 3 (STAT3) is a signaling molecule and transcription factor that plays important protective rolesintheheart.Theprotection mediated by STAT3 is attributed to its genomic actions as a transcription factor and other non-genomic roles targeting mitochondrial function and autophagy. As a transcription factor, STAT3 upregulates genes that are anti-oxidative, anti-apoptotic, and pro-angiogenic, but suppresses anti-inflammatory and anti-fibrotic genes. Its suppressive effects on gene expression are achieved through competing with other transcription Edited by: factors or cofactors. STAT3 is also linked to the modificationofmRNAexpressionprofiles Georges Nemer, American University of in cardiac cells by inhibiting or inducing miRNA. In additiontothesegenomicroles, Beirut, Lebanon STAT3 is suggested to function protectively in mitochondria, where it regulates ROS Reviewed by: production, in part by regulating the activities of the electron transport chain complexes, Fadi N. Salloum, although our recent evidence calls this role into question. Nonetheless, STAT3 is a key Virginia Commonwealth University, United States player known to be activated in the cardioprotective ischemic conditioning protocols. Yang Yang, Through these varied roles, STAT3 participates in various mechanisms that contribute Northwest University, China to cardioprotection against different heart pathologies, including myocardial infarction, *Correspondence: Gabriel Bidaux hypertrophy, diabetic cardiomyopathy, and peripartum cardiomyopathy. Understanding [email protected] how STAT3 is involved in the protective mechanisms against these different cardiac Mazen Kurdi pathologies could lead to novel therapeutic strategies to treat them. [email protected] Keywords: STAT3, cardioprotection, cardiac pathologies, myocardial infarction, genomic functions Specialty section: This article was submitted to Cardiovascular Genetics and Systems INTRODUCTION Medicine, asectionofthejournal Cardiovascular diseases are among the top challenges to global health, constituting a leading Frontiers in Cardiovascular Medicine cause for morbidity and mortality worldwide. According to theWorldHealthOrganization Received: 14 July 2019 (WHO), these diseases result in 17.5 million deaths globally per year (1). This alarming situation Accepted: 07 October 2019 increasingly excites research in the cardiovascular field, aiming to understand the mechanisms Published: 25 October 2019 underlying different cardiac pathologies. This represents a prerequisite for developing and setting Citation: therapeutic cardioprotective strategies. A remarkable body of evidence has shown that STAT3 plays Harhous Z, Booz GW, Ovize M, an important role in cardioprotection, rendering it a prominent focus of interest. It participates Bidaux G and Kurdi M (2019) An Update on the Multifaceted Roles of in mechanisms that contribute to protection against myocardial infarction, fibrosis, hypertrophy, STAT3 in the Heart. hypertension, myocarditis, diabetic cardiomyopathy, and peripartum cardiomyopathy. Several Front. Cardiovasc. Med. 6:150. previous reviews have generally addressed STAT3 functioning at the cellular level in the heart, doi: 10.3389/fcvm.2019.00150 focusing on its signaling, activation, and post-translational modifications; other reviews have Frontiers in Cardiovascular Medicine | www.frontiersin.org 1 October 2019 | Volume 6 | Article 150 Harhous et al. Multifaceted Roles of Cardiac STAT3 focused solely on a particular cardiac pathology (1, 2). This In cardiomyocytes, agonists with pathophysiological review presents a critical appraisal of the physiological and importance engage membrane receptors coupled to the pathological roles of STAT3 in the heart. We focus on the activation of JAK1 and JAK2 tyrosine kinases, and consequently involvement of STAT3 in cardiac myocyte and heart pathologies, lead to STAT3 tyrosine phosphorylation. These agonists include, starting from a general overview of STAT3 and addressing in addition to IL-6 and leukemia inhibitory factor (LIF), its activation, post-translational modifications, and different tumor necrosis factor alpha (TNFα), IFNγ, erythropoietin, and cellular pools. granulocyte-colony stimulating factor (G-CSF). The Src family kinases and bone marrow kinase on chromosome X (BMX) also STAT3 OVERVIEW induce tyrosine phosphorylation of STAT3 in cardiac cells (5). Structure Serine phosphorylation STAT3 is an 89 kDa protein encoded by the STAT3 gene. It is Serine/threonine kinases have been shown to phosphorylate 770 amino acids in length and is composed of six functional STAT3 on S727 in the cytoplasm or nucleus. The involvement domains. The NH2-terminal domain participates in higher order of serine phosphorylation in STAT3 activities was first reported complex formation. This is followed by the coiled-coil domain in 1995 by Zhang et al. who studied the importance of involved in protein-protein interactions with co-regulatorsand such phosphorylation for DNA binding (13). S727 was later transcription factors. Next is the DNA binding domain with a demonstrated through mutational studies to be required for sequence specificity for an interferon gamma (INFγ)activated maximal transcriptional activity, but not for DNA binding sequence (GAS) present in the promoter region of specific (14, 15). Serine phosphorylation may boost the transcriptional genes. Following that is the linker domain located directly activity of STAT3 by recruiting transcriptional co-factors,such before the Src homology-2 (SH2) domain, which mediates as histone acetyltransferase p300/CBP (13, 16). However, there receptor recruitment and STAT3 dimerization via intermolecular are reports as well that it may act to decrease tyrosine phosphorylated tyrosine-SH2 interactions. The transcription phosphorylation (17, 18). activation domain (TAD), located in the COOH-terminal region, Multiple kinases are responsible for S727 phosphorylation, is where regulatory phosphorylation occurs (3–5). depending on the nature of the activating signal. Mitogen STAT3 exists as two main isoforms, STAT3α (generally activated protein kinase (MAPK) family members are mainly referred to as STAT3) and STAT3β. Compared to STAT3α, reported to induce this phosphorylation in response to different STAT3β is the truncated form lacking the 55-residue C- extracellular stimuli. The MAPK family is composed of terminal transactivation domain. This splice variant can be extracellular signal-regulated kinase (ERK), induced by growth phosphorylated at the tyrosine 705 (Y705) residue, but unlike factors and cytokines, as well as JNK/stress-activated protein STAT3α lacks serine 727 (S727). STAT3β can still bind to DNA kinase and p38/HOG1 (p38 MAPK), both activated by pro- as a homo- or heterodimer (with STAT3α or other transcription inflammatory cytokines and environmental stresses (19, 20). factors) (3, 6). The role of STAT3β in the heart is unclear. Among them, the best characterized serine kinases inducing S727 The main function of STAT3 is the regulation of gene phosphorylation are ERK1/2. It is important to note that JNK transcription. STAT3 is modified at specific residues by a and p38 are considered mediators of ischemia-reperfusion injury, number of post-translational modifications with functional where they upregulate inflammatory cytokines and activate consequences, mainly acetylation and phosphorylation. In mitochondria-dependent death pathways (21). JNK and p38 addition, methylation, ubiquitination, s-nitrosylation,and MAPKs are activated by TNFα,whichisactivatedduringcardiac glutathionylation occur (5). In addition, recent evidence conditioning (22). During heart failure, the expression of the heat was reported that S-palmitoylation of STAT3 promotes its shock protein H11 kinase/Hsp22 increases as a stress-response dimerization and