Therapeutic Activation of Signal Transducer and Activator of Transcription 3 by Interleukin-11 Ameliorates Cardiac Fibrosis After Myocardial Infarction

Abstract

Background-Glycoprotein 130 is the common receptor subunit for the interleukin (IL)-6 cytokine family. Previously, we reported that pretreatment of IL-11, an IL-6 family cytokine, activates the glycoprotein 130 signaling pathway in cardiomyocytes and prevents ischemia/reperfusion injury in vivo; however, its long-term effects on cardiac remodeling after myocardial infarction (MI) remain to be elucidated. Methods and Results-MI was generated by ligating the left coronary artery in C57BL/6 mice. Real-time reverse transcription polymerase chain reaction analyses showed that IL-11 mRNA was remarkably upregulated in the hearts exposed to MI. Intravenous injection of IL-11 activated signal transducer and activator of transcription 3 (STAT3), a downstream signaling molecule of glycoprotein 130, in cardiomyocytes in vivo, suggesting that cardiac myocytes are target cells of IL-11 in the hearts. Twenty-four hours after coronary ligation, IL-11 was administered intravenously, followed by consecutive administration every 24 hours for 4 days. IL-11 treatment reduced fibrosis area 14 days after MI, attenuating cardiac dysfunction. Consistent with a previous report that STAT3 exhibits antiapoptotic and angiogenic activity in the heart, IL-11 treatment prevented apoptotic cell death of the bordering myocardium adjacent to the infarct zone and increased capillary density at the border zone. Importantly, cardiac-specific ablation of STAT3 abrogated IL-11-mediated attenuation of fibrosis and was associated with left ventricular enlargement. Moreover, with the use of cardiac-specific transgenic mice expressing constitutively active STAT3, cardiac STAT3 activation was shown to be sufficient to prevent adverse cardiac remodeling. Conclusions-IL-11 attenuated cardiac fibrosis after MI through STAT3. Activation of the IL-11/glycoprotein 130/STAT3 axis may be a novel therapeutic strategy against cardiovascular diseases. (Circulation. 2010;121:684-691.)Key Words: interleukins Ⅲ myocardial infarction Ⅲ remodeling Ⅲ signal transduction A fter myocardial injury, various kinds of neurohumoral factors and cytokines modulate cardiac remodeling. Among them, leukemia inhibitory factor (LIF) and cardiotrophin-1, which belong to the interleukin (IL)-6 family, play important roles in cardioprotection. 1,2 LIF and cardiotrophin-1 are secreted from cardiomyocytes in response to pathological stress. [3][4][5] These cytokines bind and activate LIF receptor in cardiomyocytes. 6 Activated LIF receptor makes a dimer with glycoprotein 130 (gp130), followed by activation of signal transducer and activator of transcription 3 (STAT3). 7 STAT3 activation promotes cardiomyocyte survival and vascular formation in the heart. 8 -10 Thus, cardiac activation of the gp130/STAT3 system may be a potential therapeutic strategy against cardiovascular diseases; however, therapies targeting gp130 have not been proposed. Clinical Perspective on p 691The difficulty in therapeutic activation of gp130 is derived from its receptor system. Gp130 is expressed ubiquitously as t...

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).…”

“…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). In other studies using larger animals (murine and canine) that received IL-11 after induction of ischemia, we found that IL-11 ameliorated cardiac dysfunction and reduced fibrosis in a dose-dependent manner; a dose of 16 μg/kg or more significantly preserved cardiac function (19).…”

“…Recently, we found that cardiomyocytes express a cell surface IL-11 receptor bound to a cytokine-specific transmembrane glycoprotein (gp130) and showed in a murine IR injury model that pretreatment with IL-11 provides protection against IR injury through a preconditioning effect (3). We also demonstrated that IL-11 reduces adverse cardiac remodeling, possesses antiapoptotic features, promotes angiogenesis after myocardial infarction (4), and exhibits a protective post-conditioning effect against IR injury through a signal transducer and activator of transcription protein (STAT3) activation (5). These results suggest that IL-11 may have a potential role in maintaining organ viability of the donor heart subjected to prolonged ischemia.…”

Free LIF receptor α-chain distal cytoplasmic motifs enhance Jak2-independent STAT3 phosphorylation and induce differentiation in HL-60 cells

“…have shown that stAt3 and/or stAt5 may be ideal targets for anti-cancer drugs (22,25,26). We have observed that the levels of pstAt3 are relatively high in all leukemia cells (9,22,27), which is consistent with previous reports.…”