A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subjects.
A cortactin CTTN coding SNP contributes to lung vascular permeability and inflammatory disease severity in African descent subjects.
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DOI：
10.1016/j.trsl.2022.02.002
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发表时间：
2022-06
影响因子：
7.8
通讯作者：
Dudek, Steven M.
中科院分区：
文献类型：
--
作者：
Belvitch, Patrick;Casanova, Nancy;Sun, Xiaoguang;Camp, Sara M.;Sammani, Saad;Brown, Mary E.;Mascarhenas, Joseph;Lynn, Heather;Adyshev, Djanybek;Siegler, Jessica;Desai, Ankit;Seyed-Saadat, Laleh;Rizzo, Alicai;Bime, Christian;Shekhawat, Gajendra S.;Dravid, Vinayak P.;Reilly, John P.;Jones, Tiffanie K.;Feng, Rui;Letsiou, Eleftheria;Meyer, Nuala J.;Ellis, Nathan;Garcia, Joe G. N.;Dudek, Steven M.
皮质蛋白基因（CTTN）编码一种肌动蛋白结合蛋白，对细胞骨架动力学和内皮细胞（EC）屏障的完整性至关重要，它含有与黑人患者严重哮喘相关的单核苷酸多态性（snp）。由于肺EC完整性丧失是急性呼吸窘迫综合征（ARDS）、败血症和急性胸综合征（ACS）中死亡率的主要驱动因素，我们推测CTTN snp改变EC屏障功能将与黑人患者这些类型疾病的临床结果相关。在病例对照研究中，在严重脓毒症队列（725名黑人受试者）中对非同义CTTN编码SNP Ser484Asn （rs56162978, G/ a）的评估显示与脓毒症死亡率风险增加显著相关。在有或没有ACS的镰状细胞病（SCD）受试者（177名SCD黑人受试者）的单独队列中，观察到a等位基因携带者的ACS风险和ACS严重程度（需要机械通气）显著增加。表达相关基因S484N的人肺EC表现出：1)凝血素诱导通透性后EC屏障恢复延迟；ii)临界Tyr486接触蛋白磷酸化水平降低；iii)抑制与细胞骨架调节剂nmMLCK的结合；iv)减弱EC促进屏障的板足动力学和生物物理反应。与野生型小鼠相比，Cttn+/−杂合小鼠的肺血管通透性增加，通过静脉注射含有Cttn WT转基因的脂质体而不是Cttn S484N转基因的脂质体，这种通透性显著减弱。综上所述，这些研究表明CTTN S484N编码SNP可能通过延迟血管屏障恢复导致黑人患者炎症损伤的严重程度。
The cortactin gene (CTTN), encoding an actin-binding protein critically involved in cytoskeletal dynamics and endothelial cell (EC) barrier integrity, contains single nucleotide polymorphisms (SNPs) associated with severe asthma in Black patients. As loss of lung EC integrity is a major driver of mortality in the Acute Respiratory Distress Syndrome (ARDS), sepsis, and the acute chest syndrome (ACS), we speculated CTTN SNPs that alter EC barrier function will associate with clinical outcomes from these types of conditions in Black patients. In case-control studies, evaluation of a nonsynonymous CTTN coding SNP Ser484Asn (rs56162978, G/A) in a severe sepsis cohort (725 Black subjects) revealed significant association with increased risk of sepsis mortality. In a separate cohort of sickle cell disease (SCD) subjects with and without ACS (177 SCD Black subjects), significantly increased risk of ACS and increased ACS severity (need for mechanical ventilation) was observed in carriers of the A allele. Human lung EC expressing the cortactin S484N transgene exhibited: i) delayed EC barrier recovery following thrombin-induced permeability; ii) reduced levels of critical Tyr486 cortactin phosphorylation; iii) inhibited binding to the cytoskeletal regulator, nmMLCK; and iv) attenuated EC barrier-promoting lamellipodia dynamics and biophysical responses. ARDS-challenged Cttn+/− heterozygous mice exhibited increased lung vascular permeability (compared to wild-type mice) which was significantly attenuated by IV delivery of liposomes encargoed with CTTN WT transgene but not by CTTN S484N transgene. In summary, these studies suggest that the CTTN S484N coding SNP contributes to severity of inflammatory injury in Black patients, potentially via delayed vascular barrier restoration.
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