Effects of Cardiovascular Risk Factors on Cardiac STAT3

Abstract

Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the disease. This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3 under non-ischaemic baseline conditions, and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies.

Deletion of Rap1 protects against myocardial ischemia/reperfusion injury through suppressing cell apoptosis via activation of STAT3 signaling

“…43 Therefore, mitoSTAT3 provides cardioprotection during myocardial I/R injury. 22,[43][44][45] In the present study, knockdown or knockout of Rap1 significantly increased the expression of phosphorylated STAT3 (Ser 727 ) in response to H/R or I/R, respectively. However, whether or not Rap1 knockdown/ knockout affects mitoSTAT3 level and therefore influences on ATP synthesis, mPTP opening and ROS generation are still unclear and additional studies will be needed to dissect the specific mechanisms.…”

Inhibition of EGFR-STAT3 attenuates cardiomyopathy in streptozotocin-induced type 1 diabetes

“…In contrast, there are reports that STAT3 mediates cardioprotective activity against injury from acute and chronic stresses, such as smoking, aging, hypertension and obesity (Zouein et al 2015, Pipicz et al 2018. Several studies have also reported decreased STAT3 phosphorylation and/or activation in heart tissues of various experimental models of diabetes (Pipicz et al 2018). Therefore, the exact role of STAT3 in DCM remains an enigma.…”

“…Moreover, STAT3 has been shown to be upregulated in the tubulointerstitial compartment of renal samples from diabetic patients with progressive nephropathy (Berthier et al 2009) and in animal models of diabetic nephropathy (Matsui & Meldrum 2012). In contrast, there are reports that STAT3 mediates cardioprotective activity against injury from acute and chronic stresses, such as smoking, aging, hypertension and obesity (Zouein et al 2015, Pipicz et al 2018. Several studies have also reported decreased STAT3 phosphorylation and/or activation in heart tissues of various experimental models of diabetes (Pipicz et al 2018).…”

Ageing, sex, and cardioprotection

“…This comes in addition to potential microvascular dysfunction or injury when establishing reflow. The contribution of lethal reperfusion injury to the final extent of MI has been irrefutably demonstrated in the experimental setting (Piper, Garcia-Dorado, & Ovize, 1998) and in patients with segment elevation myocardial infarction (STEMI), although here the efficacy of the therapeutic interventions has been less consistent . The time window to effectively prevent or limit myocardial injury in patients with STEMI is very short (only a few hours from the onset of chest pain), and the development of ways to reduce the myocardial consequences of ischaemia of a given severity and duration by interfering with the molecular mechanisms of ischaemic injury is a priority (Ibanez et al, 2017).…”