Cardiac signaling pathways functionally important in the heart’s response to exercise often protect the heart against pathological stress, potentially providing novel therapeutic targets. However, it is important to determine which of these pathways can be feasibly targeted . Transgenic overexpression of exercise-induced CITED4 has been shown to protect against adverse remodeling after ischemia/reperfusion injury (IRI). Here we investigated whether somatic gene transfer of CITED4 in a clinically relevant time frame could promote recovery after IRI. Cardiac CITED4 gene delivery via intravenous AAV9 injections in wild type mice led to an approximately 3-fold increase in cardiac CITED4 expression. After 4 weeks, CITED4-treated animals developed physiological cardiac hypertrophy without adverse remodeling. In IRI, delivery of AAV9-CITED4 after reperfusion resulted in a 6-fold increase in CITED4 expression 1 week after surgery, as well as decreased apoptosis, fibrosis, and inflammatory markers, culminating in a smaller scar and improved cardiac function 8 weeks after IRI, compared with control mice receiving AAV9-GFP. Somatic gene transfer of CITED4 induced a phenotype suggestive of physiological cardiac growth and mitigated adverse remodeling after ischemic injury. These studies support the feasibility of CITED4 gene therapy delivered in a clinically relevant time frame to mitigate adverse ventricular remodeling after ischemic injury.

中文翻译：

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CITED4 基因治疗可预防小鼠缺血/再灌注损伤后适应不良的心脏重塑


心脏信号通路在心脏对运动的反应中具有重要的功能，通常可以保护心脏免受病理应激，可能提供新的治疗靶点。然而，重要的是确定这些途径中的哪一条可以作为可行的目标。运动诱导的 CITED4 转基因过度表达已被证明可以防止缺血/再灌注损伤 (IRI) 后的不良重塑。在这里，我们研究了在临床相关时间范围内 CITED4 的体细胞基因转移是否可以促进 IRI 后的恢复。通过在野生型小鼠中静脉注射 AAV9 进行心脏 CITED4 基因递送，导致心脏 CITED4 表达增加约 3 倍。 4 周后，CITED4 治疗的动物出现生理性心脏肥大，但没有出现不良重塑。在 IRI 中，再灌注后递送 AAV9-CITED4 导致术后 1 周 CITED4 表达增加 6 倍，并减少细胞凋亡、纤维化和炎症标志物，最终在 IRI 后 8 周缩小疤痕并改善心功能，与接受 AAV9-GFP 的对照小鼠相比。 CITED4 的体细胞基因转移诱导了一种表明生理性心脏生长的表型，并减轻了缺血性损伤后的不良重塑。这些研究支持在临床相关时间范围内实施 CITED4 基因治疗以减轻缺血性损伤后不良心室重塑的可行性。