Therapeutic administration of IL-11 exhibits the postconditioning effects against ischemia-reperfusion injury via STAT3 in the heart

Abstract

<jats:p>Activation of cardiac STAT3 by IL-6 cytokine family contributes to cardioprotection. Previously, we demonstrated that IL-11, an IL-6 cytokine family, has the therapeutic potential to prevent adverse cardiac remodeling after myocardial infarction; however, it remains to be elucidated whether IL-11 exhibits postconditioning effects. To address the possibility that IL-11 treatment improves clinical outcome of recanalization therapy against acute myocardial infarction, we examined its postconditioning effects on ischemia/reperfusion (I/R) injury. C57BL/6 mice were exposed to ischemia (30 min) and reperfusion (24 h), and IL-11 was intravenously administered at the start of reperfusion. I/R injury mediated the activation of STAT3, which was enhanced by IL-11 administration. IL-11 treatment reduced I/R injury, analyzed by triphenyl tetrazolium chloride staining [PBS, 46.7 ± 14.4%; IL-11 (20 μg/kg), 28.6 ± 7.5% in the ratio of infarct to risk area]. Moreover, echocardiographic and hemodynamic analyses clarified that IL-11 treatment preserved cardiac function after I/R. Terminal deoxynucleotide transferase-mediated dUTP nick-end labeling staining revealed that IL-11 reduced the frequency of apoptotic cardiomyocytes after I/R. Interestingly, IL-11 reduced superoxide production assessed by in situ dihydroethidium fluorescence analysis, accompanied by the increased expression of metallothionein 1 and 2, reactive oxygen species (ROS) scavengers. Importantly, with the use of cardiac-specific STAT3 conditional knockout (STAT3 CKO) mice, it was revealed that cardiac-specific ablation of STAT3 abrogated IL-11-mediated attenuation of I/R injury. Finally, IL-11 failed to suppress the ROS production after I/R in STAT3 CKO mice. IL-11 administration exhibits the postconditioning effects through cardiac STAT3 activation, suggesting that IL-11 has the clinical therapeutic potential to prevent I/R injury in heart.</jats:p>

Cardiac-specific ablation of theSTAT3gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling

“…STAT3 iCKO mice were generated as previously described with minor modifications (20). Briefly, STAT3 flox mice were bred with transgenic mice expressing TM-inducible Cre recombinase fused to mutated estrogen receptor (MerCreMer) under the control of the cardiomyocyte-specific ␣-MHC promoter to produce ␣-MHCMerCreMer/STAT3 flox/flox mutant mice.…”

“…STAT3 plays protective roles against acute myocardial injury, such as ischemia and ischemia-reperfusion (19,20). In contrast, a recent study (10) has shown that continuous activation of STAT3 mediated by glycoprotein (gp)130 promotes adverse outcome in subacute myocardial infarction (MI) in constitutively active gp130 mutant mice.…”

Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

“…1, B and C, and Table 1). At 1 h of treatment, eight of the top 10 genes disproportionately up-regulated by mOSM-LIFR were Socs3 (26), Cxcl1 (27), Zfp36 (28), Mt2 (29), Sbno2 (30), Bcl3 (31), Junb (32), and Fos (33) (Fig. 1B).…”

The cardioprotective effect of interleukin-11 against ischemia-reperfusion injury in a heart donor model

“…Notably, administration of IL-11 after inducing myocardial infarction, which was generated by coronary ligation, ameliorated the post-infarct cardiac dysfunction. The post-ischemic treatment with IL-11 prevented cardiac fibrosis, reduced the frequency of cell death, and promoted angiogenesis (4,5).…”

“…Optimization of the dose and timing of IL-11 administration was not considered in this study but is an important topic as it may influence the outcome. What formed the basis of the present dosing strategy was the results of our previous IL-11 studies (3)(4)(5). In a study using a mouse myocardial IR injury model, the animals pretreated with 8 μg/kg of IL-11 had a significantly reduced infarct size (4).…”