Pivotal Importance of STAT3 in Protecting the Heart from Acute and Chronic Stress: New Advancement and Unresolved Issues

Zouein, Fouad A.; Altara, Raffaele; Chen, Qun; Lesnefsky, Edward J.; Kurdi, Mazen; Booz, George W.

doi:10.3389/fcvm.2015.00036

Cited by 72 publications

(82 citation statements)

References 170 publications

(257 reference statements)

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“…Signal transducer and activator of transcription 3 (STAT3) was originally identified as a transcription factor and was subsequently shown to be important in the heart for inducing a protective gene program associated with delayed preconditioning of myocardium (Kurdi and Booz, 2007; Zouein et al, 2015). The importance of STAT3 in protecting the heart from chronic stresses, such as hypertension, is not known.…”

Section: Introductionmentioning

confidence: 99%

Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension

et al. 2016

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Signal transducer and activator of transcription 3 (STAT3) protects the heart from acute ischemic stress. However, the importance of STAT3 to the heart in chronic stress, such as hypertension, is not known. To study this, we used cardiomyocyte-targeted STAT3 knockout (KO) mice and Angiotensin II (ANG II) infusion by osmotic minipumps. After 4 weeks, ANG II induced similar cardiac hypertrophy in wild type (WT) and cardiac Cre-expressing control (CTRL) mice with no impairment of cardiac function. In contrast, STAT3 KO mice exhibited reduced contractile function but similar hypertrophy to CTRL mice. Ejection fraction and fractional shortening decreased by 22.5 and 27.3%, respectively. Since STAT3 has direct protective effects on mitochondrial function, we examined rates of glucose and oleate oxidation by isolated perfused hearts using a Langendorff system. Hearts of ANG II-treated STAT3 KO and CTRL mice had similar rates of oleate oxidation as saline-infused WT mice. Rates of glucose oxidation were similar between hearts of WT plus saline and CTRL plus ANG II mice; however, glucose oxidation was increased by 66% in hearts of ANG II-treated STAT3 KO mice. The ratio of maximal ATP yield from glucose to fatty acid oxidation was 21.1 ± 3.1 in hearts of ANG II-treated STAT3 KO mice vs. 12.6 ± 2.2 in hearts of ANG II-treated CTRL mice. Lactate production was also elevated in hearts of ANG II-treated STAT3 KO mice by 162% compared to ANG II-treated CTRL mice. Our findings indicate that STAT3 is important for maintaining contractile function and metabolic homeostasis in the hypertensive heart, and STAT3 deficiency promotes a switch toward glucose utilization.

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Section: Introductionmentioning

confidence: 99%

Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension

et al. 2016

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“…Elevated eicosanoid production contributes to maladaptive changes such as inflammation and fibrosis8. In addition, interleukin-6 (IL-6) cytokine binds with glycoprotein-130 (gp130) and activates Janus kinase2/signal transducer and activator of transcription 3(JAK2/STAT3)910. STAT3 activation promotes inflammation, adverse ventricular remodeling and heart failure11.…”

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confidence: 99%

Qishen granules inhibit myocardial inflammation injury through regulating arachidonic acid metabolism

Wang

et al. 2016

Sci Rep

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Qishen granules (QSG), a traditional Chinese medicine, have been prescribed widely in the treatment of coronary heart diseases. Previous studies demonstrated that QSG had anti-inflammatory and cardio-protective effects in mice with acute myocardial infarction (AMI). However, the mechanisms by which QSG attenuate inflammation and prevent post-AMI heart failure (HF) are still unclear. In this study, we explored the anti-inflammatory mechanisms of QSG by in vitro and in vivo experiments. A novel inflammatory injury model of H9C2 cells was induced by lipopolysaccharide (LPS)-stimulated macrophage-conditioned media (CM). An animal model of AMI was conducted by ligation of left anterior descending (LAD) coronary artery in mice. We found that QSG inhibited release of cytokines from LPS-stimulated RAW 264.7 macrophages and protected H9C2 cardiac cells against CM-induced injury. In vivo results showed that QSG administration could improve cardiac functions and alter pathological changes in model of AMI. QSG regulated multiple key molecules, including phospholipases A2 (PLA2), cyclooxygenases (COXs) and lipoxygenases (LOXs), in arachidonic acid metabolism pathway. Interestingly, QSG also targeted TNF-α-NF-κB and IL-6-JAK2-STAT3 signaling pathways. Taken together, QSG achieve synergistic effects in mitigating post-AMI HF by regulating multiple targets in inflammatory pathways. This study provides insights into anti-inflammatory therapeutics in managing HF after AMI.

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“…Recent studies reported that P-STAT3 Ser is localized in mitochondria in neurons, which is independent of transcriptional regulation (Wegrzyn et al, 2009; Zouein et al, 2015). For this reason, we investigated whether OSM-induced P-STAT3 Ser is localized in mitochondria in SH-SY5Y cells.…”

Section: Resultsmentioning

confidence: 99%

“…This highlights the need to understand the pathophysiology of axonal mitochondria and the contribution of mitochondrial P-STAT3 Ser to degenerative mechanisms after SCI for novel therapeutic strategies. A number of anti-oxidant and anti-apoptotic genes are upregulated by STAT3 via nuclear P-STAT3 Tyr and mitochondrial P-STAT3 Ser to promote cell survival and reduce ROS production (Poli and Camporeale, 2015; Zouein et al, 2015). Unfortunately, the relatively short period of upregulation of both P-STAT3 Tyr and P-STAT3 Ser may not be sufficient to protect spinal cord against SCI-induced pathological progression.…”

Section: Discussionmentioning

confidence: 99%

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Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury

Park

Lin

Benveniste

et al. 2016

Experimental Neurology

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Suppressor of cytokine signaling-3 (SOCS3) expression is induced by the Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. SOCS3 then acts as a feedback inhibitor of JAK-STAT signaling. Previous studies have shown that knocking down SOCS3 in spinal cord neurons with Lentiviral delivery of SOCS3-targeting shRNA (shSOCS3) increased spinal cord injury (SCI)-induced tyrosine phosphorylation of STAT3 (P-STAT3 Tyr), which in part contributed to decreased neuronal death and demyelination as well as enhanced dendritic regeneration and protection of neuronal morphology after SCI. However, the role of serine phosphorylation of STAT3 (P-STAT3 Ser) is in large part undetermined. Our purposes of this study were to evaluate the expression patterns of P-STAT3 Ser and to explore the possible role of SOCS3 in the regulation of P-STAT3 Ser expression. Immunoblot analyses demonstrated that Oncostatin M (OSM), a member of the interleukin-6 (IL-6) cytokine family, induced both P-STAT3 Tyr and P-STAT3 Ser in SH-SY5Y cells. Subcellular fractionation further revealed that P-STAT3 Ser was localized in mitochondria. Overexpression of SOCS3 with a Lentivirus-mediated approach in SH-SY5Y cells inhibited OSM-induced P-STAT3 Ser in both cytosol and mitochondria fractions. In contrast, OSM-induced P-STAT3 Ser was further upregulated in both cytosol and mitochondria when SOCS3 was knocked down by Lentivirus-delivered shSOCS3. Using a rat T8 spinal cord complete transection model, we found that SCI induced upregulation of P-STAT3 Ser in the mitochondria of macrophages/microglia and neurons both rostral and caudal to the injury site of spinal cord. Collectively, these results suggest that SOCS3 regulation of STAT3 signaling plays critical roles in stress conditions.

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Pivotal Importance of STAT3 in Protecting the Heart from Acute and Chronic Stress: New Advancement and Unresolved Issues

Cited by 72 publications

References 170 publications

Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension

Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension

Qishen granules inhibit myocardial inflammation injury through regulating arachidonic acid metabolism

Mitochondrial STAT3 is negatively regulated by SOCS3 and upregulated after spinal cord injury

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