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Review
. 2019 Oct 25:6:150.
doi: 10.3389/fcvm.2019.00150. eCollection 2019.

An Update on the Multifaceted Roles of STAT3 in the Heart

Zeina Harhous  1   2   3 , George W Booz  4 , Michel Ovize  2   3 , Gabriel Bidaux  2   3 , Mazen Kurdi  1
Affiliations
Review

An Update on the Multifaceted Roles of STAT3 in the Heart

Zeina Harhous et al. Front Cardiovasc Med. .

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a signaling molecule and transcription factor that plays important protective roles in the heart. The protection 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 factors or cofactors. STAT3 is also linked to the modification of mRNA expression profiles in cardiac cells by inhibiting or inducing miRNA. In addition to these genomic roles, STAT3 is suggested to function protectively in mitochondria, where it regulates ROS production, in part by regulating the activities of the electron transport chain complexes, although our recent evidence calls this role into question. Nonetheless, STAT3 is a key player known to be activated in the cardioprotective ischemic conditioning protocols. Through these varied roles, STAT3 participates in various mechanisms that contribute to cardioprotection against different heart pathologies, including myocardial infarction, hypertrophy, diabetic cardiomyopathy, and peripartum cardiomyopathy. Understanding how STAT3 is involved in the protective mechanisms against these different cardiac pathologies could lead to novel therapeutic strategies to treat them.

Keywords: STAT3; cardiac pathologies; cardioprotection; genomic functions; myocardial infarction.

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Figures

Figure 1
Figure 1
The intracellular localization pattern of STAT3 affects autophagy regulation. The activation of STAT3 downstream of cytokine or tyrosine kinase receptors induces its Y705 phosphorylation and dimerization. STAT3 dimers translocate to the nucleus, where they bind to DNA in order to up- or down-regulate autophagy related genes. In addition to nuclear STAT3, unphosphorylated cytoplasmic STAT3 also regulates autophagy. Unphosphorylated cytoplasmic STAT3 sequesters FOXO and Eif2ak2. FOXO translocates into the nucleus and upregulates multiple autophagy-related genes, while Eif2ak2 phosphorylates Eif2A that regulates autophagy through its nuclear translocation. The image of DNA was adapted from Servier Medical Art (https://smart.servier.com/).
Figure 2
Figure 2
The involvement of STAT3 in the regulation of ER activity. STAT3 decreases cellular death under different conditions through its ER-dependent activity. Following I/R, JAK2-STAT3 pathway rescues SERCA expression and activity, which reduces the ER stress occurring during I/R injury. This reduces cell death and helps in inducing the infarct size. In addition, STAT3 modulates the ER-mitochondrial calcium release by directly interacting with IP3R3 and facilitating its degradation. This consequently leads to a decrease in the calcium release from ER to mitochondria, and thus causes a decrease in apoptotic cell death. The S727 STAT3 residue plays a regulatory role. The images of ER and mitochondria were adapted from Servier Medical Art (https://smart.servier.com/).
Figure 3
Figure 3
The involvement of STAT3 in cellular metabolism. STAT3 plays an important role in establishing glycolysis-dependent energy derivation, via the Warburg effect. This is mediated by several connections between STAT3 and hypoxia responsive factor 1 alpha (HIF-1α). Following oxygen deprivation (hypoxia), the levels of HIF-1α increase and cause an increase in pyruvate kinase 2 (PKM2) levels. PKM2 induces the phosphorylation of STAT3, which induces the expression of HIF-1α. In parallel, STAT3 also decreases the expression of mitochondrial genes. All these incidences finally favor anaerobic glycolysis and decrease electron transport chain activity and aerobic respiration. The images of DNA and mitochondria were adapted from Servier Medical Art (https://smart.servier.com/).
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