Myoblast sheets repaired the impaired myocardium, reduced fibrosis, and prevented remodeling in association with recruitment of hematopoietic stem cells through the release of stromal-derived factor 1 and other growth factors. Our experiment indicates a therapy for patients with severe heart failure.
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...
Our study indicated that this novel tissue-engineered vascular graft promoted in situ tissue regeneration and did not require ex vivo cell seeding, thereby conferring better patency on small-caliber vascular prostheses.
Implantation of three- and five-layered myoblast sheets yields favorable results, with better improvement of cardiac function, induction of angiogenesis, more elastic fibers, and less fibrosis. Thus, layered myoblast sheets, in optimal numbers, may attenuate adverse cardiac remodeling of the infarcted heart.
Grafting of skeletal myoblast sheets attenuated cardiac remodeling and improved cardiac performance. This novel method was feasible and effective in a large animal model, suggesting an innovative and promising strategy for treating patients with end-stage dilated cardiomyopathy.
Long-term observation showed safety and good durability of the open stent-grafting technique for aortic arch disease. This technique could be an attractive treatment option for aortic arch aneurysm with distal extension and aortic dissection requiring aortic arch replacement.
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