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Simvastatin in Endothelial Cell Barrier Regulation: A Novel Role for SAMD4A
Author(s) -
Faraj Reem,
Kelly Gabriel T.,
Feng Anlin,
Roberts Rebecca,
Kheshtchin-Kamel Nabia,
Wang Ting
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03583
Subject(s) - simvastatin , endothelial stem cell , microbiology and biotechnology , barrier function , downregulation and upregulation , gene silencing , biology , chemistry , cancer research , pharmacology , gene , biochemistry , in vitro
Acute lung injury (ALI) is a critical illness which results in significant morbidity and mortality. Endothelial barrier disruption is a key pathologic feature of ALI and serves as the main cause of life‐threatening microvascular leakage and alveolar flooding. Efforts to develop novel therapeutics have been futile with only a handful of agents available, none of which prevent or reverse endothelial barrier disruption. We believe that the answer may lie in the most unlikely of places: a cholesterol‐lowering drug. Simvastatin confers vascular protection through modulation of the endothelial barrier, attenuation of vascular leak, and promotion of endothelial repair following lung inflammation. Integrin β4 (ITGβ4, gene code: ITGB4), a transmembrane receptor protein, plays a key role in endothelial barrier regulation during ALI, and its upregulation is necessary for the enhanced barrier function seen following administration of simvastatin. Rationale The mechanism by which simvastatin up‐regulates ITGβ4 expression has not been elucidated. We sought to define the mechanistic pharmacology that controls the regulation of ITGβ4 mRNA and protein expression by simvastatin. Methods In this study, we identified potential RNA binding proteins regulated by simvastatin and inflammatory mediators that target ITGB4 using genomic analysis and molecular biology methods (western blotting and silencing), and further validated with endothelial cell biology approaches. Endothelial barrier function modulation is also investigated by electric cell‐substrate impedance sensing (ECIS). Results We have identified that Sterile Alpha Motif Domain‐Containing Protein 4A (SAMD4A), an ITGB4 RNA binding protein, is up‐regulated by LPS or TNFa, and downregulated by simvastatin. Additionally, intracellular SAMD4A levels are negatively correlated with ITGB4 mRNA levels. Silencing of SAMD4A in endothelial cells (ECs) results in increased mRNA expression of ITGB4 and enhances ITGB4‐mediated barrier function in ECs. Conclusion Our results suggest that simvastatin upregulates ITGB4 via the suppression of SAMD4A, an ITGB4 RNA binding protein, leading to enhanced endothelial cell barrier function. These findings have re‐defined the pharmacology of simvastatin on ITGB4 regulation. Furthermore, SAMD4A may serve as a novel therapeutic target for ALI via the modulation of EC barrier. Support or Funding Information This study is supported by NIH grants HL134610 and T32HL007249.