Nerve growth factor promotes cardiac repair following myocardial infarction.
Nerve growth factor promotes cardiac repair following myocardial infarction.
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DOI：
10.1161/circresaha.109.210088
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发表时间：
2010-04-16
影响因子：
20.1
通讯作者：
Emanueli C
中科院分区：
文献类型：
--
作者：
Meloni M;Caporali A;Graiani G;Lagrasta C;Katare R;Van Linthout S;Spillmann F;Campesi I;Madeddu P;Quaini F;Emanueli C
神经生长因子(NGF)促进血管生成和心肌细胞存活，两者都是心肌梗死后愈合所必需的。尽管如此，NGF对心脏修复的潜力从未被研究过。目的：明确NGF及其高亲和力受体TrkA(原肌球蛋白相关受体A)在人梗死心肌中的表达和定位，探讨内源性和工程化NGF在小鼠心肌梗死(MI)模型中的心脏作用。对心肌梗死或其他相关疾病患者的心脏标本进行NGF和TrkA免疫组织化学染色。为研究内源性神经生长因子(NGF)在心肌梗死后的作用，给MI小鼠注射NGF中和抗体(Ab-NGF)或非免疫性免疫球蛋白G(对照组)。为探讨神经生长因子的治疗潜力，将人神经生长因子基因或对照(空载体)导入小鼠心肌梗死周围。结果表明，在梗塞的人心脏中存在神经生长因子。心肌细胞和血管内皮细胞(ECs)都含有TrkA，提示NGF对人体有心血管作用。在心肌梗死小鼠中，单抗-神经生长因子抑制了天然的修复性血管生成，增加了EC和心肌细胞的凋亡，使心功能恶化。相反，NGF基因转移可改善EC和心肌细胞存活，促进新生血管形成，改善心肌血流量和心功能。促存活/促血管生成Akt/FOXO通路介导了NGF转移的治疗效果。此外，NGF过表达增加了干细胞因子(c-kit受体配体)的表达，这导致了NGF工程心脏中c-kitpos前体细胞在心肌中的丰度更高。NGF在心肌梗死后心脏具有多效性的有益作用。NGF可作为治疗性心脏再生的候选因子。
Nerve growth factor (NGF) promotes angiogenesis and cardiomyocyte survival, which are both desirable for postinfarction myocardial healing. Nonetheless, the NGF potential for cardiac repair has never been investigated. To define expression and localization of NGF and its high-affinity receptor TrkA (tropomyosin-related receptor A) in the human infarcted heart and to investigate the cardiac roles of both endogenous and engineered NGF using a mouse model of myocardial infarction (MI). Immunostaining for NGF and TrkA was performed on heart samples from humans deceased of MI or unrelated pathologies. To study the post-MI functions of endogenous NGF, a NGF-neutralizing antibody (Ab-NGF) or nonimmune IgG (control) was given to MI mice. To investigate the NGF therapeutic potential, human NGF gene or control (empty vector) was delivered to the murine periinfarct myocardium. Results indicate that NGF is present in the infarcted human heart. Both cardiomyocytes and endothelial cells (ECs) possess TrkA, which suggests NGF cardiovascular actions in humans. In MI mice, Ab-NGF abrogated native reparative angiogenesis, increased EC and cardiomyocyte apoptosis and worsened cardiac function. Conversely, NGF gene transfer ameliorated EC and cardiomyocyte survival, promoted neovascularization and improved myocardial blood flow and cardiac function. The prosurvival/proangiogenic Akt/Foxo pathway mediated the therapeutic benefits of NGF transfer. Moreover, NGF overexpression increased stem cell factor (the c-kit receptor ligand) expression, which translated in higher myocardial abundance of c-kitpos progenitor cells in NGF-engineered hearts. NGF elicits pleiotropic beneficial actions in the post-MI heart. NGF should be considered as a candidate for therapeutic cardiac regeneration.