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Endothelial Cell Protein Targeting by Myeloperoxidase-Derived 2-Chlorofatty Aldehyde.
Shubha Shakya1,2, Roger A Herr1,2, Haley L Carlson1,2
1Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Antioxidants (Basel, Switzerland)
|May 28, 2022
Summary
Neutrophils release oxidants that damage cells. This study shows 2-chlorofatty aldehyde (2-ClFALD), a neutrophil-derived lipid, preferentially modifies proteins involved in cell adhesion and junctions, potentially causing endothelial dysfunction.
Area of Science:
- Biochemistry
- Cell Biology
- Pathology
Background:
- Neutrophils are key players in disease-related injury and repair.
- Myeloperoxidase-derived oxidants, like HOCl, can injure endothelial cells.
- HOCl generates electrophilic lipids, 2-chlorofatty aldehyde (2-ClFALD) and 2-chlorofatty acid (2-ClFA), which modify proteins.
Purpose of the Study:
- To investigate protein modification specifically by 2-ClFALD under non-reducing conditions.
- To compare protein modification by 2-ClFALD and its oxidation product, 2-ClFA.
- To identify proteins targeted by 2-ClFALD in endothelial cells.
Main Methods:
- Utilized ω-alkyne analogs of 2-ClFALD (2-ClHDyA) and 2-ClFA (2-ClHyA) for protein modification studies.
- Employed shotgun proteomics to analyze 2-ClHDyA-modified proteins in EA.hy926 and human lung microvascular endothelial cells.
- Performed over-representation analysis to identify enriched protein categories.
Main Results:
- Demonstrated that 2-ClFALD preferentially modifies proteins compared to 2-ClFA.
- Identified adherens junction, cell adhesion molecule binding, and cell substrate junction categories as significantly enriched in 2-ClHDyA-modified proteins.
- Suggests a mechanism for 2-ClFALD-induced endothelial barrier dysfunction.
Conclusions:
- 2-ClFALD is a potent protein modifier in endothelial cells.
- Targeting of junctional proteins by 2-ClFALD may underlie endothelial barrier dysfunction.
- Further research into these protein modifications could reveal therapeutic targets for inflammatory diseases.
