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抑制prolyl氧酶域蛋白质可以促进治疗性再血管化
Céline Loinard1, Amandine Ginouvès, José Vilar
1Paris Cardiovascular Research Center, INSERM U970, Hôpital Européen Georges Pompidou, Université Paris 5, Paris, France.
抑制prolyl氧酶域蛋白 (PHDs),特别是PHD3,通过上调缺氧诱导因子1 (HIF-1) 来增强治疗性再血管化. 这项研究证实,HIF-1信号传递对于促进缺血后血管生长至关重要.
科学领域:
- 分子生物学分子生物学
- 血管生物学 血管生物学
- 缺血症研究 缺血症研究
背景情况:
- 低氧诱导因子 (HIF) 的子单元由依赖氧气的酸酶蛋白域蛋白 (PHDs) 调节.
- PHDs (PHD1,PHD2,PHD3) 针对HIF进行降解.
- 研究PHD抑制以提高HIF的调节,以促进后缺血性新血管化.
研究的目的:
- 为了确定通过HIF上调抑制PHD是否促进后缺血性新血管化.
- 评估特定的PHD异型 (PHD1,PHD2,PHD3) 在这个过程中的作用.
- 确认HIF-1信号在调解益血管性影响中的必要性.
主要方法:
- 小鼠接受了右大腿动脉绑定.
- 针对HIF-1alpha,PHD1,PHD2或PHD3.3的短发针RNA (shRNA) 的体内电转移.
- 对照组接受了不相关的shRNA (shCON).
- 对PHDs,HIF-1alpha,VEGF-A,eNOS,MCP-1和巨细胞透的mRNA和蛋白质水平的分析.
- 对新血管和足 perfusion 的评估.
主要成果:
- 沉默PHDs (特别是PHD2和PHD3) 暂时下调PHD mRNA/蛋白质和上调HIF-1alpha.
- 促进血管生成因子 (VEGF-A, eNOS) 的升级和增强巨细胞的透 (shPHD2/shPHD3).
- 在shPHD2和shPHD3治疗的小鼠中,血管密度,毛细血管密度和足部 perfusion 的显著增加.
- 同时服用shHIF-1alpha可废除shPHD3的作用,证实了HIF-1的依赖性.
结论:
- 直接抑制PHDs,特别是PHD3,可以促进治疗性再血管化.
- HIF-1信号通路对于调解PHD沉默的益血管效应至关重要.
- 针对PHDs代表了治疗缺血性疾病的潜在策略.
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