细胞穿透肽偶联到内皮一氧化氮合酶序列改变内皮通透性。

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Tissue Barriers Pub Date : 2022-10-02 DOI:10.1080/21688370.2021.2017226
Stephen R Koch, Ryan J Stark
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引用次数: 1

摘要

通过使用细胞穿透肽(CPP)序列将货物运送到细胞是靶向治疗的一个丰富的研究领域。内皮是覆盖身体每条血管的细胞层,对于内皮细胞来说,一种关键酶内皮一氧化氮合酶(eNOS)的缺失或改变,在严重的感染性挑战中有助于内皮细胞的健康。虽然eNOS的有益作用通常被认为是通过产生一氧化氮介导的,但理论上认为,eNOS通过五基基RRKRK基序与调控途径结合可以起到一定的保护作用。我们假设使用常见的CPPs递送eNOS-RRKRK肽序列可以防止革兰氏阴性脂多糖(LPS)。通过跨内皮电阻(TEER)测量,将eNOS-RRKRK序列与CPP天线基(AP)结合可以降低lps诱导的培养人微血管内皮细胞(HMVECs)通透性的影响。细胞因子的产生也有适度的减少,但观察到AP单独显著损害lps诱导的内皮通透性和细胞因子的产生。相比之下,CPP转录反式激活因子(TAT)本身没有显著改变内皮炎症。当TAT与eNOS-RRKRK序列偶联时,对lps诱导的通透性仍有保护作用,但细胞因子的产生并未减少。这些数据表明,eNOS的RRKRK序列可以对lps介导的内皮炎症提供一些no无关的保护,但是保护程度高度依赖于用于货物递送的CPP类型。
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Cell penetrating peptides coupled to an endothelial nitric oxide synthase sequence alter endothelial permeability.

Delivery of cargo to cells through the use of cell-penetrating peptide (CPP) sequences is an area of rich investigation for targeted therapeutics. Specific to the endothelium, the layer of cells that cover every blood vessel in the body, the loss or alteration of a key enzyme, endothelial nitric oxide synthase (eNOS), is known to contribute to endothelial health during severe, infectious challenge. While the beneficial effects of eNOS are often thought to be mediated through the generation of nitric oxide, some protection is theorized to be through eNOS binding to regulatory pathways via a pentabasic RRKRK motif. We hypothesized that delivery of the eNOS-RRKRK peptide sequence using common CPPs would allow protection against gram-negative lipopolysaccharide (LPS). Combination of the eNOS-RRKRK sequence to the CPP antennapedia (AP) reduced the impact of LPS-induced permeability in cultured human microvascular endothelial cells (HMVECs) as measured by transendothelial electrical resistance (TEER). There was also a modest reduction in cytokine production, however it was observed that AP alone significantly impaired LPS-induced endothelial permeability and cytokine production. In comparison, the CPP trans-activator of transcription (TAT) did not significantly alter endothelial inflammation by itself. When TAT was coupled to the eNOS-RRKRK sequence, protection against LPS-induced permeability was still demonstrated, however cytokine production was not reduced. These data demonstrate that the RRKRK sequence of eNOS can offer some NO-independent protection against LPS-mediated endothelial inflammation, however the degree of protection is highly dependent on the type of CPP utilized for cargo delivery.

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来源期刊
Tissue Barriers
Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
6.60
自引率
6.50%
发文量
25
期刊介绍: Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.
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