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.
Highlights
Cardiovascular diseases are among the top challenges to global health, constituting a leading cause for morbidity and mortality worldwide
We focus on the involvement of Signal transducer and activator of transcription 3 (STAT3) in cardiac myocyte and heart pathologies, starting from a general overview of STAT3 and addressing its activation, post-translational modifications, and different cellular pools
STAT3 represents a crucial molecule for the maintenance of heart function, under physiological and pathological conditions
Summary
Cardiovascular diseases are among the top challenges to global health, constituting a leading cause for morbidity and mortality worldwide. It was originally assumed that STAT3-dependent biological effects are due to its potency as a transcription factor capable of regulating gene expression, evidence of its mitochondrial presence and activity has emerged [40, 41] In this context, STAT3 has been reported to control electron transport chain (ETC) activity and adenosine 5′ -triphosphate (ATP) production [37, 42,43,44,45,46]. In the context of IR injury, Meier et al recently revealed that oxidative stress and cytokines, which are supposedly important mediators of IR injury, dynamically regulated mitochondrial STAT3 Their results highlighted that H2O2 and different cytokines induced a rapid loss of STAT3 (within few minutes) from mitochondria, and a rapid recovery dependent on the phosphorylation of the S727 residue. A number of other factors have been demonstrated to activate STAT3 in the context of IR injury with a protective effect observed, including TNF-α, sphingosine-1-phosphate, HDL, ethanolamine, and melatonin [1]
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