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

• Published in: Circulation (New York, N.Y.) N.Y.), 2010-02, Vol.121 (5), p.684-691
• Main Authors: OBANA, Masanori, MAEDA, Makiko, AZUMA, Junichi, FUJIO, Yasushi, TAKEDA, Koji, HAYAMA, Akiko, MOHRI, Tomomi, YAMASHITA, Tomomi, NAKAOKA, Yoshikazu, KOMURO, Issei, TAKEDA, Kiyoshi, MATSUMIYA, Goro
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Coronary heart disease; Cytokine Receptor gp130 - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Fibrosis; Gene Expression Regulation - drug effects; Heart; Interleukin-11 - biosynthesis; Interleukin-11 - pharmacology; Interleukin-6 - metabolism; Medical sciences; Mice; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - pathology; Neovascularization, Physiologic - drug effects; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; STAT3 Transcription Factor - metabolism; Time Factors
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circulationaha.109.893677

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. 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. 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.