Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction
Conditional Transgenic Expression of Fibroblast Growth Factor 9 in the Adult Mouse Heart Reduces Heart Failure Mortality After Myocardial Infarction
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DOI：
10.1161/circulationaha.110.989665
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发表时间：
2011-02-08
期刊：
影响因子：
37.8
通讯作者：
Wollert, Kai C.
中科院分区：
文献类型：
--
作者：
Korf-Klingebiel, Mortimer;Kempf, Tibor;Wollert, Kai C.
成纤维细胞生长因子9 （FGF9）由骨髓细胞分泌，在一项临床试验中已被证明可改善心肌梗死（MI）后的收缩功能。FGF9在胚胎发育过程中促进心脏血管形成，但仅在成人心脏中微弱表达。方法和结果：我们采用基于α -肌球蛋白重链启动子的四环素应答型双转基因系统来检测FGF9在成年心肌中的条件表达是否支持心肌梗死后的适应性。在假手术小鼠中，转基因FGF9刺激左心室肥厚，微血管扩张，并保持收缩和舒张功能。冠状动脉结扎后，转基因FGF9增强了非梗死左心室心肌的肥厚，微血管密度增加，间质纤维化减少，胎儿基因表达减弱，收缩功能改善。转基因FGF9显著降低心肌梗死后心力衰竭死亡率，而心肌破裂率不受影响。心肌梗死后腺病毒FGF9基因转移同样促进左心室肥厚，改善收缩功能，降低心力衰竭死亡率。在机制上，FGF9刺激内皮细胞的增殖和网络形成，但在体外对新生或成年大鼠心肌细胞没有直接的肥厚作用。然而，fgf9刺激的内皮细胞上清液通过旁分泌释放骨形态发生蛋白6诱导心肌细胞肥大。与此观察结果一致，FGF9转基因小鼠心肌中骨形态发生蛋白6的表达及其下游靶点SMAD1/5的磷酸化水平升高。结论：FGF9的条件表达促进心肌血管化和肥厚，增强收缩功能，降低心肌梗死后的心力衰竭死亡率。这些观察结果表明，FGF9在心肌梗死后具有以前未被认识到的治疗潜力。
Background-Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart.Methods and Results-We used a tetracycline-responsive binary transgene system based on the alpha-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice.Conclusions-Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI. (Circulation. 2011; 123: 504-514.)