Membrane raft redox signalling contributes to endothelial dysfunction and vascular remodelling of thoracic aorta in angiotensin II‐infused rats

Abstract

New Findings What is the central question of this study?Is the membrane raft redox signalling pathway involved in blood pressure increase, endothelial dysfunction and vascular remodelling in an angiotensin II‐induced hypertensive animal model? What is the main finding and its importance?The membrane raft redox signalling pathway was involved in endothelial dysfunction and medial remodelling in angiotensin II‐induced hypertension. Abstract The membrane raft (MR) redox pathway is characterized by NADPH oxidase activation via the clustering of its subunits through lysosome fusion and the activation of acid sphingomyelinase (ASMase). Our previous study shows that the MR redox signalling pathway is associated with angiontensin II (AngII)‐induced production of reactive oxygen species (ROS) and endothelial dysfunction in rat mesenteric arteries. In the present study, we hypothesized that this signalling pathway is involved in blood pressure increase, endothelial dysfunction and vascular remodelling in an AngII‐induced hypertensive animal model. Sixteen‐week‐old male Sprague–Dawley rats were subjected to AngII infusion for 2 weeks with or without treatment with the lysosome fusion inhibitor bafilomycin A1 and ASMase inhibitor amitriptyline. After treatments, aortas were harvested for further study. The results showed that the MR redox signalling pathway was activated as indicated by the increase of MR formation, ASMase activity and ROS production in aorta from AngII‐infused rats compared with that from control rats. MR formation and ROS production were significantly inhibited in thoracic aorta from AngII‐induced rats treated with bafilomycin A1 and amitriptyline. Both treatments significantly attenuated blood pressure increase, endothelial dysfunction and vascular remodelling including medial hypertrophy, and increased collagen and fibronectin deposition in thoracic aortas from AngII‐infused rats. Finally, both treatments significantly prevented the increase of inflammatory factors including monocyte chemotactic protein 1, intercellular adhesion molecule 1 and tumour necrosis factor α in thoracic aorta from AngII‐infused rats. In conclusion, the present study demonstrates that the MR redox signalling pathway was involved in endothelial dysfunction and medial remodelling in AngII‐induced hypertension.

Marked elevations in lung and plasma ceramide in COVID-19 linked to microvascular injury

“…While several enzymatic pathways of sphingolipid metabolism regulate intracellular ceramide production, the circulating ceramide pool is contributed by release of ceramide-enriched extracellular vesicles from plasma membranes of various cells, an event that, during stress, involves ASMase ( 37 ). Therefore, the C16:0-ceramide elevations in COVID-19 plasma may reflect endothelial cell ASMase activation by oxidative stress ( 38 ), inflammatory cytokines ( 39 ), or excess angiotensin II ( 40 ) that characterize severe SARS-CoV-2 infection ( 41 , 42 ). The subsequent activation of ASMase downstream of initial injurious responses to SARS-CoV-2 is consistent with the observation that endothelial injury follows that of the epithelium in severe COVID-19 ( 43 ).…”

Naringenin Inhibits Acid Sphingomyelinase-Mediated Membrane Raft Clustering to Reduce NADPH Oxidase Activation and Vascular Inflammation

“…the cell physiology. 2,3,7,10 We established that the inhibitory effect of naringenin on foam cell formation is dependent on the lipid raft translocation of TLR4. To gain more insight into the role of lipid rafts in the effects of naringenin on foam cell formation, we incubated oxLDL-stimulated macrophages with different doses of naringenin, and the lipid rafts were labeled with FITC-CTXB.…”

“…4 The assembly of functionally active NOX2 is dependent on lipid rafts and is a key step in lipid raft-redox signaling. 5 The NOX2-dependent lipid raft redox signaling is promoted by ASMase/ceramide and is involved in the regulation of endothelial dysfunction, 6,7 chronic periodontitis, 8 bronchial epithelial cells activation, and vascular remodeling 9,10 Naringenin (4′,5,7-trihydroxy flavonone) is a plant bioflavonoid that is abundantly found in citrus and other fruits, such as strawberries and grapefruits. Naringenin possesses a variety of bioactivities, including antioxidative and antiinflammatory activities, and is effective in alleviating various diseases, such as neurodegeneration, diabetes mellitus, and intestinal inflammation.…”

“…The assembly of functionally active NOX2 is dependent on lipid rafts and is a key step in lipid raft-redox signaling . The NOX2-dependent lipid raft redox signaling is promoted by ASMase/ceramide and is involved in the regulation of endothelial dysfunction, , chronic periodontitis, bronchial epithelial cells activation, and vascular remodeling , …”

Mechanism of Vascular Toxicity in Rats Subjected to Treatment with a Tyrosine Kinase Inhibitor

“…The superoxide-sensitive fluorescent dye dihydroethidium (DHE; MedChemExpress, HY-D0079) was used to estimate the level of O 2 − as previously reported [18]. Thoracic aortas were embedded in Tissue-Tek®O.C.T.™ (Sakura Finetek, 4583) and frozen sections were cut into 10 µm thick sections with a cryostat (Leica CM1510 S, Leica Biosystems).…”