Regulation of STAT3 and its role in cardioprotection by conditioning: focus on non-genomic roles targeting mitochondrial function

Abstract

Ischemia–reperfusion injury (IRI) is one of the biggest challenges for cardiovascular researchers given the huge death toll caused by myocardial ischemic disease. Cardioprotective conditioning strategies, namely pre- and post-conditioning maneuvers, represent the most important strategies for stimulating pro-survival pathways essential to preserve cardiac health. Conditioning maneuvers have proved to be fundamental for the knowledge of the molecular basis of both IRI and cardioprotection. Among this evidence, the importance of signal transducer and activator of transcription 3 (STAT3) emerged. STAT3 is not only a transcription factor but also exhibits non-genomic pro-survival functions preserving mitochondrial function from IRI. Indeed, STAT3 is emerging as an influencer of mitochondrial function to explain the cardioprotection phenomena. Studying cardioprotection, STAT3 proved to be crucial as an element of the survivor activating factor enhancement (SAFE) pathway, which converges on mitochondria and influences their function by cross-talking with other cardioprotective pathways. Clearly there are still some functional properties of STAT3 to be discovered. Therefore, in this review, we highlight the evidence that places STAT3 as a promoter of the metabolic network. In particular, we focus on the possible interactions of STAT3 with processes aimed at maintaining mitochondrial functions, including the regulation of the electron transport chain, the production of reactive oxygen species, the homeostasis of Ca2+ and the inhibition of opening of mitochondrial permeability transition pore. Then we consider the role of STAT3 and the parallels between STA3/STAT5 in cardioprotection by conditioning, giving emphasis to the human heart and confounders.

Stat3 Signaling Pathway: A Future Therapeutic Target for Bone-Related Diseases

“…Stat3 has become a research hotspot because of its essential function during diverse biological processes such as proliferation, differentiation, anti-apoptosis, inflammatory response, and angiogenesis ( Cheng et al, 2020 ; Tian et al, 2020 ; He et al, 2021 ). In previous researches, Stat3 was considered as a critical signaling molecule for immune escape, atherosclerosis, malignancy and cardiac injury ( Huynh et al, 2017 ; Chen et al, 2019 ; Comita et al, 2021 ; Zhang et al, 2022 ). Over-activation of Stat3 will lead to poor prognosis and drug resistance in osteosarcoma ( Liu et al, 2021 ).…”

A TRICk to Improve the Effectiveness of RIC: Role of Limb Temperature in Enhancing the Effectiveness of Remote Ischemic Conditioning

“…The SAFE pathway, including the signal transducer and transcription activator (STAT)-3 and STAT5, and the RISK pathway, including PI3K/Akt, can play a central role in RIC cardioprotection—in both humans and mice [ 20 ]. Indeed, in STAT5 knockout mice it was found that RIC-induced infarct size reduction occurs via the PI3K/Akt pathway and the anti-apoptotic cascade, thus confirming the importance of RISK in rodents [ 21 ].…”

Mitochondrial Damage in Myocardial Ischemia/Reperfusion Injury and Application of Natural Plant Products

“…Cardioprotective conditioning strategies are strategies for activating prosurvival pathways and keep cardiac health. Signal transducer and activator of transcription 3 (STAT3) are not only the transcription factors but also exhibit nongenomic prosurvival functions preserving mitochondrial function from I/R injury [ 87 ]. It has been reported that the activity of MCU could be influenced by STAT3 [ 88 ].…”