Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis and Muscle Recovery in Preclinical Model of PAD.
Estrogen-Related Receptor Gamma Gene Therapy Promotes Therapeutic Angiogenesis and Muscle Recovery in Preclinical Model of PAD.
复制标题
雌激素相关受体 γ 基因治疗促进 PAD 临床前模型中的治疗性血管生成和肌肉恢复。
DOI：
10.1161/jaha.122.028880
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发表时间：
2023-08-15
影响因子：
5.4
通讯作者：
Narkar, Vihang A. A.
中科院分区：
文献类型：
--
作者：
Sopariwala, Danesh H. H.;Rios, Andrea S. S.;Saley, Addison;Kumar, Ashok;Narkar, Vihang A. A.
外周动脉疾病和严重肢体缺血是与血管功能不全、氧化代谢功能障碍和肢体肌病相关的心血管并发症。通过转基因小鼠研究，雌激素相关受体γ（ERRγ）已成为旁分泌血管生成和氧化代谢的双重调节因子。本研究的目的是在外周动脉疾病/严重肢体缺血的临床前模型中，研究缺血后通过基因治疗肌内靶向ERRγ是否促进缺血性恢复。开发了腺相关病毒9（AAV 9）Esrrg基因递送载体，并首次通过肌内注射在小鼠骨骼肌中进行测试。AAV 9-Esrrg显著增加ERRγ蛋白表达，诱导血管生成和氧化基因，并增强C57 Bl/6 J小鼠骨骼肌中的毛细血管密度和琥珀酸脱氢酶氧化代谢活性。接下来，通过单侧股血管结扎在小鼠中诱导后肢缺血，然后在损伤后24小时肌内AAV 9-Esrrg（或AAV 9-绿色荧光蛋白）基因递送。ERRγ过表达增加了缺血性新生血管和内皮活化标志物，并显著改善了使用激光多普勒血流仪测量的缺血性血运重建。ERRγ过表达可恢复缺血心肌琥珀酸脱氢酶的氧化代谢能力，这与线粒体呼吸复合物蛋白表达增加有关。最重要的是，肌纤维大小与数量的定量显示，AAV 9-Esrrg恢复了肌原纤维大小并减轻了缺血诱导的肌病。这些结果表明，肌肉内AAV 9-Esrrg递送在后肢缺血后挽救了缺血性病理，强调了Esrrg基因治疗或药理学激活可能是用于管理外周动脉疾病/严重肢体缺血的有前景的策略。
Peripheral arterial disease and critical limb ischemia are cardiovascular complications associated with vascular insufficiency, oxidative metabolic dysfunction, and myopathy in the limbs. Estrogen‐related receptor gamma (ERRγ) has emerged as a dual regulator of paracrine angiogenesis and oxidative metabolism through transgenic mouse studies. Here our objective was to investigate whether postischemic intramuscular targeting of ERRγ via gene therapy promotes ischemic recovery in a preclinical model of peripheral arterial disease/critical limb ischemia. Adeno‐associated virus 9 (AAV9) Esrrg gene delivery vector was developed and first tested via intramuscular injection in murine skeletal muscle. AAV9‐Esrrg robustly increased ERRγ protein expression, induced angiogenic and oxidative genes, and boosted capillary density and succinate dehydrogenase oxidative metabolic activity in skeletal muscles of C57Bl/6J mice. Next, hindlimb ischemia was induced via unilateral femoral vessel ligation in mice, followed by intramuscular AAV9‐Esrrg (or AAV9‐green fluorescent protein) gene delivery 24 hours after injury. ERRγ overexpression increased ischemic neoangiogenesis and markers of endothelial activation, and significantly improved ischemic revascularization measured using laser Doppler flowmetry. Moreover, ERRγ overexpression restored succinate dehydrogenase oxidative metabolic capacity in ischemic muscle, which correlated with increased mitochondrial respiratory complex protein expression. Most importantly, myofiber size to number quantification revealed that AAV9‐Esrrg restores myofibrillar size and mitigates ischemia‐induced myopathy. These results demonstrate that intramuscular AAV9‐Esrrg delivery rescues ischemic pathology after hindlimb ischemia, underscoring that Esrrg gene therapy or pharmacological activation could be a promising strategy for the management of peripheral arterial disease/critical limb ischemia.