Amphipathic Helical Peptide L37-pA Protects Against Lung Vascular Endothelial Dysfunction Caused by Truncated Oxidized Phospholipids via Antagonism with CD36 Receptor.
Pratap KarkiYue LiChen-Ou ZhangYunbo KeKamoltip PromnaresAnna A BirukovaThomas L EggermanAlexander V BocharovKonstantin G BirukovPublished in: American journal of respiratory cell and molecular biology (2023)
Generation of bioactive truncated oxidized phospholipids (Tr-OxPLs) from oxidation of cell membrane or circulating lipoproteins is a common feature of various pathological states. Scavenger receptor CD36 is involved in lipid transport and acts as a ligand for Tr-OxPLs. Interestingly, both Tr-OxPLs and CD36 are involved in endothelial dysfunction-derived acute lung injury but precise mechanistic connections remain unexplored. In the present study, we investigated the role of CD36 in mediating pulmonary endothelial cell (EC) dysfunction caused by Tr-OxPLs. Our results demonstrated that Tr-OxPLs: KOdia-PC, Paz-PC, PGPC, PON-PC, POV-PC, and Lyso-PC caused an acute EC barrier disruption as revealed by measurements of transendothelial electrical resistance and VE-cadherin immunostaining. More importantly, a synthetic amphipathic helical peptide L37pA targeting human CD36 strongly attenuated Tr-OxPLs-induced EC permeability. L37pA also suppressed Tr-OxPLs-induced endothelial inflammatory activation monitored by mRNA expression of inflammatory cytokines/chemokines and adhesion molecules. In addition, L37pA blocked Tr-OxPL-induced NF-B activation and tyrosine phosphorylation of Src kinase and VE-cadherin. Src inhibitor SU6656 attenuated KOdiaPC- induced EC permeability and inflammation, but inhibition of toll-like receptors TLR1, TLR2, TLR4, and TLR6 had no such protective effects. CD36 knockout mice were more resistant to Tr-OxPLs-induced lung injury and L37pA was equally effective in ameliorating Tr-OxPL-induced vascular leak and lung inflammation in mice as determined by Evans blue extravasation assay and total cells and protein content in BAL. Altogether, these results demonstrate an essential role of CD36 in mediating Tr-OxPL-induced EC dysfunction and suggest a strong therapeutic potential of CD36 inhibitory peptides in mitigating lung injury and inflammation.
Keyphrases
- cell adhesion
- high glucose
- endothelial cells
- oxidative stress
- diabetic rats
- drug induced
- immune response
- inflammatory response
- machine learning
- nk cells
- pulmonary hypertension
- intensive care unit
- metabolic syndrome
- high resolution
- lipopolysaccharide induced
- escherichia coli
- mass spectrometry
- induced apoptosis
- cell proliferation
- cell death
- lps induced
- stress induced
- liver failure
- atomic force microscopy