Carolin Lerchenmüller, Margaret H Hastings, Charles P Rabolli, Fynn Betge, Mani Roshan, Laura X Liu, Xiaojun Liu, Chiara Heß, Jason D Roh, Colin Platt, Vassilios Bezzerides, Martin Busch, Hugo A Katus, Norbert Frey, Patrick Most, Anthony Rosenzweig
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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. 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引用次数: 0
摘要
在心脏对运动的反应中起重要作用的心脏信号通路往往能保护心脏免受病理应激,从而有可能提供新的治疗靶点。然而,重要的是要确定这些通路中哪些可以在体内进行靶向治疗。研究表明,转基因过表达运动诱导的 CITED4 可保护心脏免受缺血再灌注损伤(IRI)后的不良重塑。在此,我们研究了体细胞基因转移 CITED4 是否能在与临床相关的时间范围内促进 IRI 后的恢复。通过静脉注射AAV9,野生型小鼠的心脏CITED4基因表达量增加了3倍。四周后,经 CITED4 处理的动物出现生理性心脏肥大,但无不良重塑。在 IRI 中,与接受 AAV9-GFP 的对照组相比,在再灌注后转运 AAV9-CITED4 的小鼠在术后一周 CITED4 的表达增加了 6 倍,同时减少了细胞凋亡、纤维化和炎症标志物,最终在 IRI 八周后疤痕变小,心脏功能得到改善。CITED4 的体细胞基因转移诱导了一种表明心脏生理性生长的表型,并减轻了缺血性损伤后的不良重塑。这些研究支持了在临床相关时间内进行 CITED4 基因治疗以减轻缺血性损伤后心室不良重塑的可行性。
CITED4 gene therapy protects against maladaptive cardiac remodeling after ischemia/reperfusion injury in mice.
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 in vivo. 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.
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.