A cell permeable peptide targeting the intracellular loop 2 of endothelin B receptor reduces pulmonary hypertension in a hypoxic rat model.
A cell permeable peptide targeting the intracellular loop 2 of endothelin B receptor reduces pulmonary hypertension in a hypoxic rat model.
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DOI：
10.1371/journal.pone.0081309
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hill N
中科院分区：
文献类型：
--
作者：
Green DS;Rupasinghe C;Warburton R;Wilson JL;Sallum CO;Taylor L;Yatawara A;Mierke D;Polgar P;Hill N
细胞渗透性肽（CPP）有助于细胞穿过疏水质膜摄取靶向货物。CPP介导的受体信号传导基序的货物递送提供了调节特异性受体引发的信号传导级联的机会。内皮素-1受体（ETA和ETB）是肺动脉高压（PAH）患者拮抗剂治疗的靶点。这些疗法取得了成功，但伴随着不良反应。此外，与靶向特定信号传导级联的CPP不同，拮抗剂靶向受体的整个功能。使用偏向性拮抗ETB受体的细胞内环2（ICB 2）的CPP策略，我们证明了大鼠缺氧性肺动脉高压（HPH）的钝化，包括肺动脉压，右心室肥大和肺血管重构的指数。此外，在注射后用IC2B肽处理的肺动脉的离体分析表明Akt和ERK活化显著降低。这两种激酶与PAH的标志细胞增殖和血管收缩密切相关。总之，这些观察结果说明了ETB受体参与HPH，并进一步为PAH治疗中的新型CPP为基础的策略提供了基础，最终不仅能够靶向ET-1，而且还能够靶向参与PAH发展的其他因素。
Cell permeable peptides (CPP) aid cellular uptake of targeted cargo across the hydrophobic plasma membrane. CPP-mediated cargo delivery of receptor signaling motifs provides an opportunity to regulate specific receptor initiated signaling cascades. Both endothelin-1 receptors, ETA and ETB, have been targets of antagonist therapies for individuals with pulmonary arterial hypertension (PAH). These therapies have had success but have been accompanied by adverse reactions. Also, unlike the CPP which target specific signaling cascades, the antagonists target the entire function of the receptor. Using the CPP strategy of biased antagonism of the ETB receptor’s intracellular loop 2 (ICB2), we demonstrate blunting of hypoxic pulmonary hypertension (HPH) in the rat, including indices of pulmonary arterial pressure, right ventricular hypertrophy and pulmonary vascular remodeling. Further, ex vivo analysis of the pulmonary artery treated with the IC2B peptide upon injection manifests marked reductions in Akt and ERK activation. Both kinases have been intimately related to cell proliferation and vascular contraction, the hallmarks of PAH. These observations in sum illustrate an involvement of the ETB receptor in HPH and furthermore provide a basis for a novel, CPP-based, strategy in the treatment of PAH, ultimately able to target not only ET-1, but also other factors involved in the development of PAH.
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