ROCK1 inhibitor stabilizes E-cadherin and improves barrier function in experimental necrotizing enterocolitis
| Autor: | Carrie Yuan, Samuel C. Klonoski, Douglas R. Wood, Guillermo Ares, Catherine J. Hunter, Christie Buonpane |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Pyridines Physiology Gene Expression Regulation Enzymologic Adherens junction 03 medical and health sciences 0302 clinical medicine Cronobacter sakazakii Downregulation and upregulation Enterocolitis Necrotizing Physiology (medical) medicine Animals Humans ROCK1 Enzyme Inhibitors Barrier function Cytochrome P-450 Enzyme Inducers rho-Associated Kinases Intestinal permeability Hepatology Chemistry Cadherin Enterobacteriaceae Infections Gastroenterology Cadherins medicine.disease Amides Intestinal epithelium digestive system diseases Rats Intestines 030104 developmental biology Animals Newborn 030220 oncology & carcinogenesis Necrotizing enterocolitis Cancer research Caco-2 Cells Research Article |
| Zdroj: | Am J Physiol Gastrointest Liver Physiol |
| ISSN: | 1522-1547 0193-1857 |
| DOI: | 10.1152/ajpgi.00195.2019 |
| Popis: | Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of newborns. Although incompletely understood, NEC is associated with intestinal barrier dysfunction. E-cadherin, an adherens junction, is a protein complex integral in maintaining normal barrier homeostasis. Rho-associated protein kinase-1 (ROCK1) is a kinase that regulates the E-cadherin complex, and p120-catenin is a subunit of the E-cadherin complex that has been implicated in stabilizing the cadherin complex at the plasma membrane. We hypothesized that E-cadherin is decreased in NEC and that inhibition of ROCK1 would protect against adherens junction disruption. To investigate this, a multimodal approach was used: In vitro Caco-2 model of NEC (LPS/TNFα), rap pup model (hypoxia + bacteria-containing formula), and human intestinal samples. E-cadherin was decreased in NEC compared with controls, with relocalization from the cell border to an intracellular location. ROCK1 exhibited a time-dependent response to disease, with increased early expression in NEC and decreased expression at later time points and disease severity. Administration of ROCK1 inhibitor (RI) resulted in preservation of E-cadherin expression at the cell border, preservation of intestinal villi on histological examination, and decreased apoptosis. ROCK1 upregulation in NEC led to decreased association of E-cadherin to p120 and increased intestinal permeability. RI helped maintain the stability of the E-cadherin-p120 complex, leading to improved barrier integrity and protection from experimental NEC.NEW & NOTEWORTHY This paper is the first to describe the effect of ROCK1 on E-cadherin expression in the intestinal epithelium and the protective effects of ROCK inhibitor on E-cadherin stability in necrotizing enterocolitis. |
| Databáze: | OpenAIRE |
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