Understanding STAT3 signaling in cardiac ischemia

O’Sullivan, Katie E.; Breen, Edmond J.; Gallagher, Helen C.; Buggy, Donal J.; Hurley, JP

doi:10.1007/s00395-016-0543-8

Cited by 47 publications

(47 citation statements)

References 111 publications

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“…Transcription factor binding site analysis of up- and down-regulated mRNAs in our experimental MI model identified a specific enrichment pattern of several putatively important transcription factors in the heart after MI. Many of these transcription factors have been shown to play crucial roles in pathophysiology of MI [ 44 , 45 ] . Among them are the homeobox transcription factor Nkx2-5 and the zink finger transcription factors Klf4.…”

Section: Discussionmentioning

confidence: 99%

Analysis of region specific gene expression patterns in the heart and systemic responses after experimental myocardial ischemia

et al. 2017

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AimsIschemic myocardial injury leads to the activation of inflammatory mechanisms and results in ventricular remodeling. Although great efforts have been made to unravel the molecular and cellular processes taking place in the ischemic myocardium, little is known about the effects on the surrounding tissue and other organs. The aim of this study was to determine region specific differences in the myocardium and in distant organs after experimental myocardial infarction by using a bioinformatics approach.Methods and ResultsA porcine closed chest reperfused acute myocardial infarction model and mRNA microarrays have been used to evaluate gene expression changes. Myocardial infarction changed the expression of 8903 genes in myocardial-, 856 in hepatic- and 338 in splenic tissue. Identification of myocardial region specific differences as well as expression profiling of distant organs revealed clear gene-regulation patterns within the first 24 hours after ischemia. Transcription factor binding site analysis suggested a strong role for Kruppel like factor 4 (Klf4) in the regulation of gene expression following myocardial infarction, and was therefore investigated further by immunohistochemistry. Strong nuclear Klf4 expression with clear region specific differences was detectable in porcine and human heart samples after myocardial infarction.ConclusionApart from presenting a post myocardial infarction gene expression database and specific response pathways, the key message of this work is that myocardial ischemia does not end at the injured myocardium. The present results have enlarged the spectrum of organs affected, and suggest that a variety of organ systems are involved in the co-ordination of the organism´s response to myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

Analysis of region specific gene expression patterns in the heart and systemic responses after experimental myocardial ischemia

et al. 2017

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“…Fibronectin is another extracellular matrix, and the fibronectin extra domain-A (ED-A) is crucial in myofibrosis [ 9 ]. STAT3 has been documented to promote the transcription of target genes, including CCN2 [ 10 ] and other genes [ 11 ], via direct interactions with consensus sites in the promoter regions. Recently, drug-induced peroxisome proliferator-activated receptor δ (PPARδ) activation has been shown to attenuate STAT3 expression for the improvement of DCM in rats [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rh2 Improves Cardiac Fibrosis via PPARδ–STAT3 Signaling in Type 1-Like Diabetic Rats

Hsu

Niu

et al. 2017

IJMS

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Ginsenoside Rh2 (Rh2) is an active principal ingredient contained in ginseng (Panax ginseng Meyer), a medicinal herb used to enhance health worldwide. The present study is designed to investigate the effect of Rh2 on myocardial fibrosis in diabetic rats. In a streptozotocin-induced model of type-1 diabetic rats (STZ-diabetic rats), the increased fasting blood glucose levels and heart weight/body weight (HW/BW) ratio were substantially alleviated by Rh2. Moreover, Rh2 improved cardiac performance in STZ-diabetic rats. Histological results from Masson staining showed that Rh2 attenuated cardiac fibrosis in STZ-diabetic rats. The effects of Rh2 were reversed by GSK0660 at a dose sufficient to inhibit peroxisome proliferator-activated receptor δ (PPARδ) in STZ-diabetic rats. The role of PPARδ was subsequently investigated in vitro. Rh2 restored the decreased PPARδ expression level in high glucose-cultured cardiomyocytes. Moreover, increased protein levels of fibrotic signals, including signal transducer and activator of transcription 3 (STAT3), connective tissue growth factor (CCN2) and fibronectin, were reduced by Rh2 in high glucose-cultured cardiomyocytes. These effects of Rh2 were reversed by GSK0660 or siRNA specific for PPARδ Taken together, PPARδ activation may inhibit STAT3 activation to reduce CCN2 and fibronectin expression in diabetic rats with cardiac fibrosis. Moreover, Rh2 improves cardiac function and fibrosis by increasing PPARδ signaling. Therefore, Rh2 is suitable to develop as an alternative remedy for cardiac fibrosis.

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“…STAT3 is important for cardiomyocyte function via modulation of mitochondrial and transcriptional responses, and, beyond that role, it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts [17]. In addition, the latest study from our group has demonstrated that phosphorylation of STAT3 can activate Akt and that both play critical roles in the activation of endothelial nitric oxide synthase (eNOS) and the subsequent attenuation of myocardial IR injury [18].…”

Section: Introductionmentioning

confidence: 99%

Remote Limb Ischaemic Postconditioning Protects Against Myocardial Ischaemia/Reperfusion Injury in Mice: Activation of JAK/STAT3-Mediated Nrf2-Antioxidant Signalling

Gao

Zhan

Yang

et al. 2017

Cell Physiol Biochem

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Background: This study aimed to evaluate the protective effect and mechanisms of remote limb ischaemic postconditioning (RIPostC) against myocardial ischaemia/reperfusion (IR) injury. Methods: Male mice underwent 45 min of coronary artery occlusion followed by 2 h of reperfusion. RIPostC was achieved by three cycles of 5 min of ischaemia and 5 min of reperfusion in the left hind limb at the start of the reperfusion period. After 2 h of cardiac reperfusion, myocardial infarct size, cardiac enzyme release, apoptosis and oxidative stress were assessed. Protein expression and phosphorylation were measured by Western blotting. Results: RIPostC significantly decreased cardiac IR injury, as reflected by reduced infarct size and cellular apoptosis (22.9 ± 3.3% vs 40.9 ± 6.2% and 13.4% ± 3.1% vs 26.2% ± 3.1%, respectively, both P < 0.01) as well as plasma creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH) release (21.97 ± 4.08 vs 35.86 ± 2.91 ng/ml and 6.17 ± 0.58 vs 8.37 ± 0.89 U/ml, respectively, both P < 0.01) compared with the IR group. RIPostC significantly increased the phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.01). In addition, RIPostC elevated the nuclear translocation of Nrf2 and the expression of HO-1 and reduced myocardial oxidative stress (P < 0.05). Interestingly, pretreatment with the JAK/STAT3 inhibitor AG490 blocked the cardioprotective effect of RIPostC accompanied by decreased phosphorylation of myocardial STAT3, Akt and eNOS (P < 0.05), decreased nuclear translocation of Nrf2 and expression of HO-1, as well as increased oxidative stress (P < 0.05). Conclusion: RIPostC attenuates apoptosis and protects against myocardial IR injury, possibly through the activation of JAK/STAT3-mediated Nrf2-antioxidant signalling.

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Understanding STAT3 signaling in cardiac ischemia

Cited by 47 publications

References 111 publications

Analysis of region specific gene expression patterns in the heart and systemic responses after experimental myocardial ischemia

Analysis of region specific gene expression patterns in the heart and systemic responses after experimental myocardial ischemia

Ginsenoside Rh2 Improves Cardiac Fibrosis via PPARδ–STAT3 Signaling in Type 1-Like Diabetic Rats

Remote Limb Ischaemic Postconditioning Protects Against Myocardial Ischaemia/Reperfusion Injury in Mice: Activation of JAK/STAT3-Mediated Nrf2-Antioxidant Signalling

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