Eicosapentaenoic acid reduced levels of angiotensin converting enzyme and caveolin-1 in pulmonary endothelial cells following cytokine treatment

[[125I]Tyr8]Bradykinin is degraded by angiotensin-converting enzyme to [125I]Tyr-Arg. The reaction product can be separated completely and recovered nearly quantitatively from unchanged substrate by cation-exchange chromatography. Thus it is possible to use [[125I]Tyr8]bradykinin at high specific radioactivity (about 400Ci/mmol) to measure the small quantities of angiotensin-converting enzyme encountered in small-scale cultures of pulmonary endothelial cells.

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Angiotensin-Converting Enzyme 2 Inhibits Apoptosis of Pulmonary Endothelial Cells During Acute Lung Injury Through Suppressing SMAD2 Phosphorylation

Cellular Physiology and Biochemistry ◽

10.1159/000374025 ◽

2015 ◽

Vol 35 (6) ◽

pp. 2203-2212 ◽

Cited By ~ 14

Author(s):

Yong Ji ◽

Fengying Gao ◽

Bo Sun ◽

Jing Hao ◽

Zhenwei Liu

Keyword(s):

Endothelial Cells ◽

Acute Lung Injury ◽

Lung Injury ◽

Angiotensin Converting Enzyme ◽

Cell Apoptosis ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Pulmonary Endothelial Cells ◽

Smad2 Phosphorylation ◽

Induced Apoptosis

Background/Aims: Angiotensin converting enzyme 2 (ACE2) has an established role in suppressing the severity of acute lung injury (ALI), especially when it was applied together with transplantation of human umbilical cord mesenchymal stem cells (uMSCs). Although the effects of ACE2 in ALI are believed to mainly result from its role in hydrolyzing angiotensin II (AngII), which subsequently reduces the vascular tension and subsequent pulmonary accumulation of inflammatory cells, we and others have recently reported a possible role of ACE2 in suppressing the ALI-induced apoptosis of pulmonary endothelial cells. However, the underlying mechanisms remain undetermined. Methods: Here, we analyzed the alteration in lung injury severity in ALI after ACE2, by histology and inflammatory cytokine levels. We analyzed apoptosis-associated proteins in lung after ALI, as well as in cultured endothelial cells treated with nitric oxide (NO). We overexpressed SMAD7 to inhibit SMAD2 signaling in cultured endothelial cells and examined its effects on NO-induced cell apoptosis. Results: ACE2 alleviated severity of lung injury after ALI. ACE2 significantly decreased the ALI-induced apoptosis of pulmonary cells in vivo, and ACE2 protected endothelial cells against NO-induced apoptosis in vitro. NO induced phosphorylation of a key factor of transforming growth factor β (TGF β) receptor signaling, SMAD2, which could be dose-dependently inhibited by ACE2. Inhibition of SMAD2 phosphorylation through expression of its inhibitor SMAD7 significantly inhibited NO-induced cell apoptosis, without need for ACE2. Conclusion: Our data suggest that ACE2-mediated AngII degradation may inhibit AngII-mediated SMAD2-phophorylation, possibly through a TGFβ-independent manner, which subsequently suppresses the ALI-induced cell death. Our results thus reveal a novel molecular pathway that controls the pathogenesis of ALI.

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Subcellular localization of pulmonary antiotensin-converting enzyme (kininase II)

Biochemical Journal ◽

10.1042/bj1460497 ◽

1975 ◽

Vol 146 (2) ◽

pp. 497-499 ◽

Cited By ~ 226

Author(s):

J W Ryan ◽

U S Ryan ◽

D R Schultz ◽

C Whitaker ◽

A Chung ◽

...

Keyword(s):

Electron Microscopy ◽

Endothelial Cells ◽

Plasma Membrane ◽

Angiotensin Converting Enzyme ◽

Luminal Surface ◽

Converting Enzyme ◽

Rat Lung ◽

Angiotensin I ◽

Kininase Ii ◽

Pulmonary Endothelial Cells

Goat antibodies to pig lung angiotensin-converting enzyme (kininase II) were conjugated to microperoxidase. Rat lung tissue, previously incubated with non-immune goat serum, was incubated with the antibody-microperoxidase conjugate and then with H2O2 and 3,3-diaminobenzidine. Electron microscopy revealed reaction product on the plasma membrane and caveolae of endothelial cells, especially those of capillaries and venules. These results support the hypothesis that angiotensin I and bradykinin are metabolized by enzymes on the luminal surface of pulmonary endothelial cells.

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Eicosapentaenoic Acid Reduced Expression of Inflammatory Proteins in Vascular Endothelial Cells during Cytokine Treatment in Vitro

Metabolism ◽

10.1016/j.metabol.2020.154556 ◽

2021 ◽

Vol 116 ◽

pp. 154556

Author(s):

Samuel C.R. Sherratt ◽

Deepak L. Bhatt ◽

R. Preston Mason

Keyword(s):

Endothelial Cells ◽

Eicosapentaenoic Acid ◽

Vascular Endothelial Cells ◽

Vascular Endothelial ◽

Cytokine Treatment ◽

Inflammatory Proteins

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Non-opiate receptor mediated effects of morphine on the activity of angiotensin-converting enzyme (ACE) of endothelial cells

Regulatory Peptides ◽

10.1016/0167-0115(94)90454-5 ◽

1994 ◽

Vol 54 (1) ◽

pp. 189-190

Author(s):

MF Melzig ◽

G Heder ◽

W-E Siems ◽

J Zipper

Keyword(s):

Endothelial Cells ◽

Angiotensin Converting Enzyme ◽

Opiate Receptor ◽

Converting Enzyme ◽

Mediated Effects

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The Possible Therapeutic Actions of Peroxisome Proliferator-Activated Receptor α(PPARα) Agonists,PPARγ Agonists,3-Hydroxy-3- Methylglutaryl Coenzyme A (HMG-CoA)Reductase Inhibitors,Angiotensin Converting Enzyme (ACE)Inhibitors and Calcium (Ca)-Antagonists on Vascular Endothelial Cells

Current Drug Targets - Cardiovascular & Hematological Disorders ◽

10.2174/1568006043481329 ◽

2004 ◽

Vol 4 (1) ◽

pp. 35-52 ◽

Cited By ~ 6

Author(s):

Ikuo Inoue ◽

Shigehiro Katayama

Keyword(s):

Endothelial Cells ◽

Angiotensin Converting Enzyme ◽

Vascular Endothelial Cells ◽

Peroxisome Proliferator ◽

Vascular Endothelial ◽

Converting Enzyme ◽

Peroxisome Proliferator Activated Receptor ◽

Reductase Inhibitors ◽

Hmg Coa Reductase Inhibitors ◽

Coa Reductase

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Effect of angiotensin-converting-enzyme inhibition on bradykinin metabolism by vascular endothelial cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1993.264.5.h1493 ◽

1993 ◽

Vol 264 (5) ◽

pp. H1493-H1497 ◽

Cited By ~ 3

Author(s):

M. Grafe ◽

C. Bossaller ◽

K. Graf ◽

W. Auch-Schwelk ◽

C. R. Baumgarten ◽

...

Keyword(s):

Endothelial Cells ◽

Angiotensin Converting Enzyme ◽

Vascular Endothelial Cells ◽

Ace Inhibition ◽

Angiotensin Converting Enzyme Inhibition ◽

Dependent Manner ◽

Converting Enzyme ◽

Concentration Dependent Manner ◽

Cell Monolayers ◽

Converting Enzyme Inhibition

The degradation of bradykinin by angiotensin-converting-enzyme (ACE) activity in cultured human endothelial cells was studied by direct measurement of bradykinin and by its effect on the release of endothelium-derived relaxing factors. The half-life of exogenous bradykinin (10,000 pg/ml) was calculated from the decay of the bradykinin concentration as 46 +/- 2 min in cell monolayers, 133 +/- 15 min in conditioned medium, and 24 +/- 2 min in homogenates. Most of the bradykinin-degrading activity in cell monolayers could be inhibited in a concentration-dependent manner by the ACE inhibitors lisinopril, ramiprilat, and captopril. Bradykinin-degrading activity was released into the culture medium containing one-fourth of the bradykinin-degrading activity found in the presence of cell monolayers. In cell homogenates higher unspecific bradykinin-degrading activities were present. The functional consequence of bradykinin degradation was demonstrated by the potentiating effect of ramiprilat on the generation of endothelium-derived relaxing factors nitric oxide and prostacyclin from endothelial cells. The study supports the concept of increased vasodilatory effects of bradykinin during ACE inhibition.

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SARS-CoV-2 Spike Protein Induces Degradation of Junctional Proteins That Maintain Endothelial Barrier Integrity

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.687783 ◽

2021 ◽

Vol 8 ◽

Author(s):

Somasundaram Raghavan ◽

Divya Borsandra Kenchappa ◽

M. Dennis Leo

Keyword(s):

Endothelial Cells ◽

Angiotensin Converting Enzyme ◽

Spike Protein ◽

Endothelial Barrier ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Barrier Integrity ◽

Junctional Proteins ◽

Junction Protein ◽

Junctional Protein

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the Angiotensin converting enzyme 2 (ACE2) receptor present on the cell surface to enter cells. Angiotensin converting enzyme 2 is present in many cell types including endothelial cells, where it functions to protect against oxidative damage. There is growing evidence to suggest that coronavirus disease (COVID-19) patients exhibit a wide range of post-recovery symptoms and shows signs related to cardiovascular and specifically, endothelial damage. We hypothesized that these vascular symptoms might be associated with disrupted endothelial barrier integrity. This was investigated in vitro using endothelial cell culture and recombinant SARS-CoV-2 spike protein S1 Receptor-Binding Domain (Spike). Mouse brain microvascular endothelial cells from normal (C57BL/6 mice) and diabetic (db/db) mice were used. An endothelial transwell permeability assay revealed increased permeability in diabetic cells as well as after Spike treatment. The expression of VE-Cadherin, an endothelial adherens junction protein, JAM-A, a tight junctional protein, Connexin-43, a gap junctional protein, and PECAM-1, were all decreased significantly after Spike treatment in control and to a greater extent, in diabetic cells. In control cells, Spike treatment increased association of endothelial junctional proteins with Rab5a, a mediator of the endocytic trafficking compartment. In cerebral arteries isolated from control and diabetic animals, Spike protein had a greater effect in downregulating expression of endothelial junctional proteins in arteries from diabetic animals than from control animals. In conclusion, these experiments reveal that Spike-induced degradation of endothelial junctional proteins affects endothelial barrier function and is the likely cause of vascular damage observed in COVID-19 affected individuals.

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