BMP9调节内皮细胞的分泌基因,驱动肺高血压
Ying Zhong1, Peiran Yang1,2, Luca Troncone1
1Cardiovascular Research Center, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
向内皮细胞中的BMP9信号,通过抑制关键疾病相关基因,有效治疗肺动脉高血压 (PAH). 这种方法为PAH患者提供了一个有前途的治疗策略.
科学领域:
- 心血管生物学 心血管生物学
- 分子医学是分子医学.
- 内分泌学 在内分泌学.
背景情况:
- 骨形态遗传蛋白9 (BMP9) 是一种参与内皮功能和肺动脉高血压 (PAH) 发病的细胞因子.
- 在GDF2 (编码为BMP9) 中的功能丧失突变与遗传性PAH有关,这表明BMP9在维持内皮静止的作用.
- 在实验性肺高血压 (PH) 模型中,BMP9的激动性和对抗性都显示出潜力,因此需要澄清BMP9的确切作用和治疗潜力.
研究的目的:
- 解决BMP9对肺血管疾病的特定贡献.
- 评估BMP9作为PAH的潜在治疗标.
- 调查BMP9影响PH的机制以及准其信号通路的影响.
主要方法:
- 在实验性PH模型 (SUGEN-hypoxia,monocrotaline) 中使用了复合BMP9,BMP9/BMP10连接体陷 (ALK1-Fc),抗BMP9中和抗体,以及活性蛋白/GDF/BMP连接体陷 (ACTRIIA-Fc/sotatercept).
- 采用单核RNA测序 (snRNA-Seq) 来分析肺血管细胞中的转录活性 (SMAD1/5,SMAD2/3) 和差异基因表达 (DEGs).
- 对人类PAH肺组织和实验PH模型进行了多原子分析,并对PAH患者衍生的肺微血管内皮细胞 (PMVECs) 进行了转录组分析.
- 对PMVECs和肺动脉光滑肌细胞 (PASMCs) 进行了共同培养研究,以评估膜信号效应.
主要成果:
- 与二硫化物结合的,产域复合的BMP9并没有对实验性PH进行保护,与之前的不完全结合形式的发现不同.
- 选择性和非选择性BMP9对抗性在PH模型中证明了预防和治疗益处.
- 反BMP9抗体和ACTRIIA-Fc对血液动力学,右心室缩和血管重塑表现出类似的效果.
- snRNA-Seq揭示了抗BMP9和ACTRIIA-Fc之间的重叠机制,包括抑制SMAD1/5和SMAD2/3信号和内皮细胞中非常相似的DEGs (r=0.83,p=2.54e-43).
- 鉴定出BMP9对于调节人类和实验PAH中过度表达的内皮基因产物 (例如CXCL12,PDGF-BB,EDN1,COL18A1,IGFBP4) 是至关重要的.
- 刺激BMP9的PMVEC对PASMC表型表现出近效应,主要由内皮衍生CXCL12介导.
结论:
- 内皮细胞BMP9信号传递是血管活性内皮细胞基因产物的关键调节者,影响PAH中PASMC表型.
- 针对BMP9信号,通过抗BMP9抗体或像ACTRIIA-Fc这样的配体陷,代表了一个共享的治疗机制.
- 选择性抑制内皮BMP9血管性信号传递为人类PAH提供了可行的治疗策略.
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