Galindo Cristi L, Kasasbeh Ehab, Murphy Abigail, Ryzhov Sergey, Lenihan Sean, Ahmad Farhaan A, Williams Philip, Nunnally Amy, Adcock Jamie, Song Yanna, Harrell Frank E, Tran Truc-Linh, Parry Tom J, Iaci Jen, Ganguly Anindita, Feoktistov Igor, Stephenson Matthew K, Caggiano Anthony O, Sawyer Douglas B, Cleator John H
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (C.L.G., E.K., A.M., S.R., S.L., F.A.A., P.W., A.N., J.A., T.L.T., I.F., D.B.S.).
Department of Biostatistics, Vanderbilt University, Nashville, TN (Y.S., F.E.H.).
J Am Heart Assoc. 2014 Oct 23;3(5):e000773. doi: 10.1161/JAHA.113.000773.
Neuregulin-1β (NRG-1β) is a growth factor critical for cardiac development and repair with therapeutic potential for heart failure. We previously showed that the glial growth factor 2 (GGF2) isoform of NRG-1β improves cardiac function in rodents after myocardial infarction (MI), but its efficacy in a large animal model of cardiac injury has not been examined. We therefore sought to examine the effects of GGF2 on ventricular remodeling, cardiac function, and global transcription in post-MI swine, as well as potential mechanisms for anti-remodeling effects.
MI was induced in anesthetized swine (n=23) by intracoronary balloon occlusion. At 1 week post-MI, survivors (n=13) received GGF2 treatment (intravenous, biweekly for 4 weeks; n=8) or were untreated (n=5). At 5 weeks post-MI, fractional shortening was higher (32.8% versus 25.3%, P=0.019), and left ventricular (LV) end-diastolic dimension lower (4.5 versus 5.3 cm, P=0.003) in GGF2-treated animals. Treatment altered expression of 528 genes, as measured by microarrays, including collagens, basal lamina components, and matricellular proteins. GGF2-treated pigs exhibited improvements in LV cardiomyocyte mitochondria and intercalated disk structures and showed less fibrosis, altered matrix structure, and fewer myofibroblasts (myoFbs), based on trichrome staining, electron microscopy, and immunostaining. In vitro experiments with isolated murine and rat cardiac fibroblasts demonstrate that NRG-1β reduces myoFbs, and suppresses TGFβ-induced phospho-SMAD3 as well as αSMA expression.
These results suggest that GGF2/NRG-1β prevents adverse remodeling after injury in part via anti-fibrotic effects in the heart.
神经调节蛋白-1β（NRG-1β）是一种对心脏发育和修复至关重要的生长因子，对心力衰竭具有治疗潜力。我们之前表明，NRG-1β的胶质细胞生长因子2（GGF2）亚型可改善啮齿动物心肌梗死后的心脏功能，但尚未在大型心脏损伤动物模型中检验其疗效。因此，我们试图研究GGF2对心肌梗死后猪心室重构、心脏功能和整体转录的影响，以及抗重构作用的潜在机制。
通过冠状动脉内球囊闭塞法在麻醉的猪（n=23）中诱导心肌梗死。心肌梗死后1周，存活的猪（n=13）接受GGF2治疗（静脉注射，每两周一次，共4周；n=8）或不接受治疗（n=5）。心肌梗死后5周，接受GGF2治疗的动物的缩短分数更高（32.8%对25.3%，P=0.019），左心室舒张末期内径更低（4.5对5.3 cm，P=0.003）。通过微阵列测量，治疗改变了528个基因的表达，包括胶原蛋白、基膜成分和基质细胞蛋白。基于三色染色、电子显微镜和免疫染色，接受GGF2治疗的猪左心室心肌细胞线粒体和闰盘结构得到改善，纤维化减少，基质结构改变，成肌纤维细胞（肌成纤维细胞）减少。对分离的小鼠和大鼠心脏成纤维细胞进行的体外实验表明，NRG-1β可减少肌成纤维细胞，并抑制TGFβ诱导的磷酸化SMAD3以及αSMA表达。
这些结果表明，GGF2/NRG-1β部分通过对心脏的抗纤维化作用来预防损伤后的不良重构。
