Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis

Uhal, Bruce D.; Dang, MyTrang; Dang, Vinh; Llatos, Roger; Cano, Esteban; Abdul-Hafez, Amal; Markey, Jonathan C.; Piasecki, Christopher C.; Molina-Molina, María

doi:10.1183/09031936.00015612

Cited by 62 publications

(53 citation statements)

References 41 publications

(65 reference statements)

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“…2B, complete inhibition of cathepsin D enzymatic activity by pepstatin A supports the specificity of the enzyme assay for aspartyl protease induction by MG132. Figure 3 shows that ER stress induced by MG132 also downregulated the ANGII-degrading enzyme ACE-2, beginning at a concentration of 7.5 M. ACE-2 was also downregulated by the alternate proteasome inhibitor CLBL if applied to A549 cells cultured at a higher cell density, suggesting that the downregulation was due to proteasome inhibition rather than density-dependent effects on cell proliferation (21). In agreement with that interpretation, the G100S BRICHOS domain mutant of SP-C, when transfected into A549 cells alongside wild-type SP-C in the same plasmid, also reduced ACE-2, especially the low molecular weight (MW) active form of the enzyme.…”

Section: Resultsmentioning

confidence: 99%

“…3) each downregulated ACE-2 and did so at two different cell densities, each cultured in the absence of growth factors (serumfree medium). Moreover, the proteasome inhibition caused by these agents is known to inhibit, not stimulate, the cell proliferation that downregulated ACE-2 in the absence of these agents (21). For this reason, it is suggested here that ER stress constitutes another mechanism responsible for the downregulation of ACE-2 in fibrotic human lung.…”

Section: L38 Angiotensin 1-7 Abrogates Apoptosis Induced By Er Stressmentioning

confidence: 87%

“…A recent report by our group found that ACE-2 expression by AECs is highly dependent on cell cycle status, with the highest expression being exhibited by quiescent cells but loss of ACE-2 expression occurring with induction of cell proliferation (21). Given the high fraction of AECs that are proliferating in the fibrosing human lung (i.e., the "hyperplastic epithelium" in IPF), it was speculated that the previously observed loss of ACE-2 expression in the lungs of patients with IPF might be due simply to the high fraction of AECs that are proliferating.…”

Section: L38 Angiotensin 1-7 Abrogates Apoptosis Induced By Er Stressmentioning

confidence: 99%

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Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1–7

Uhal

Nguyen

Dang

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Earlier work showed that apoptosis of alveolar epithelial cells (AECs) in response to endogenous or xenobiotic factors is regulated by autocrine generation of angiotensin (ANG) II and its counterregulatory peptide ANG1-7. Mutations in surfactant protein C (SP-C) induce endoplasmic reticulum (ER) stress and apoptosis in AECs and cause lung fibrosis. This study tested the hypothesis that ER stress-induced apoptosis of AECs might also be regulated by the autocrine ANGII/ANG1-7 system of AECs. ER stress was induced in A549 cells or primary cultures of human AECs with the proteasome inhibitor MG132 or the SP-C BRICHOS domain mutant G100S. ER stress activated the ANGII-generating enzyme cathepsin D and simultaneously decreased the ANGII-degrading enzyme ACE-2, which normally generates the antiapoptotic peptide ANG1-7. TAPI-2, an inhibitor of ADAM17/TACE, significantly reduced both the activation of cathepsin D and the loss of ACE-2. Apoptosis of AECs induced by ER stress was measured by assays of mitochondrial function, JNK activation, caspase activation, and nuclear fragmentation. Apoptosis induced by either MG132 or the SP-C BRICHOS mutant G100S was significantly inhibited by the ANG receptor blocker saralasin and was completely abrogated by ANG1-7. Inhibition by ANG1-7 was blocked by the specific mas antagonist A779. These data show that ER stress-induced apoptosis is mediated by the autocrine ANGII/ANG1-7 system in human AECs and demonstrate effective blockade of SP-C mutation-induced apoptosis by ANG1-7. They also suggest that therapeutic strategies aimed at administering ANG1-7 or stimulating ACE-2 may hold potential for the management of ER stress-induced fibrotic lung disorders.idiopathic pulmonary fibrosis; BRICHOS domain mutations; ADAM17/ TACE; substituted peptide receptor antagonists APOPTOSIS OF ALVEOLAR EPITHELIAL cells (AECs) is increasingly being recognized as a critical event that initiates and propagates fibrosis in the lung parenchyma (20). The concept that AEC death was a critical determinant of fibrosis vs. normal repair was first proposed many years ago on the basis of two-hit toxicological experiments that demonstrated that fibrogenesis could be induced by experimental delay of epithelial repair after lung injury (1, 6), regardless of the presence or absence of inflammation. More recent evidence in support of this theory was found in the ability of caspase inhibitors (8, 25) or genetic deletion of apoptosis signaling molecules (2) to block fibrogenesis subsequent to lung injuries aimed at the epithelium (5).Understanding the regulation of AEC apoptosis is therefore critical to understanding the pathogenesis of lung fibrosis. Earlier work from this laboratory found that endogenous (24, 26) or xenobiotic inducers of AEC apoptosis (11) activate the autocrine synthesis of angiotensin (ANG)II from its precursor angiotensinogen (AGT) as well as its subsequent enzymatic processing to the mature peptide ANGII, all by the AEC itself. Further work demonstrated that the autocrine production of ANGII by AEC...

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Section: Resultsmentioning

confidence: 99%

Section: L38 Angiotensin 1-7 Abrogates Apoptosis Induced By Er Stressmentioning

confidence: 87%

Section: L38 Angiotensin 1-7 Abrogates Apoptosis Induced By Er Stressmentioning

confidence: 99%

See 1 more Smart Citation

Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1–7

Uhal

Nguyen

Dang

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…11A). It is well known that ACE2 expression is cell cycle dependent and is very sensitive to the cell confluence levels [10]. To exclude the influence of cell confluence, we performed the experiment in controlled 50-70% cell confluence.…”

Section: Resultsmentioning

confidence: 99%

“…ACE2 activity and expression level were reported to be severely down regulated or absent in proliferating alveolar epithelial cell lines A549 and MLE-12, while its activity and expression level went much higher in quiescent A549 and MLE-12 cells [10]. Loss of ACE2 in mice enhanced the expression of genes that were induced by hypoxia and elevated mice serum Ang Ⅱ, causing endothelial dysfunction, vasoconstriction and cardiac hypoperfusion [11, 12].…”

Section: Introductionmentioning

confidence: 99%

A Human Long Non-Coding RNA ALT1 Controls the Cell Cycle of Vascular Endothelial Cells Via ACE2 and Cyclin D1 Pathway

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: ALT1 is a novel long non-coding RNA derived from the alternatively spliced transcript of the deleted in lymphocytic leukemia 2 (DLEU2). To date, ALT1 biological roles in human vascular endothelial cells have not been reported. Methods: ALT1 was knocked down by siRNAs. Cell proliferation was analyzed by cck-8. The existence and sequence of human ALT1 were identified by 3’ rapid amplification of cDNA ends. The interaction between lncRNA and proteins was analyzed by RNA-Protein pull down assay, RNA immunoprecipitation, and mass spectrometry analysis. Results: ALT1 was expressed in human umbilical vein endothelial cells (HUVECs). The expression of ALT1 was significantly downregulated in contact-inhibited HUVECs and in hypoxia-induced, growth-arrested HUVECs. Knocking down of ALT1 inhibited the proliferation of HUVECs by G0/G1 cell cycle arrest. We observed that angiotensin converting enzyme Ⅱ(ACE2) was a direct target gene of ALT1. Knocking-down of ALT1 or its target gene ACE2 could efficiently decrease the expression of cyclin D1 via the enhanced ubiquitination and degradation, in which HIF-1α and protein von Hippel-Lindau (pVHL) might be involved. Conclusion: The results suggested the human long non-coding RNA ALT1 is a novel regulator for cell cycle of HUVECs via ACE2 and cyclin D1 pathway.

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Aerosol or droplet: critical definitions in the COVID‐19 era

Kohanski

Palmer

Cohen

2020

Int Forum Allergy Rhinol

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To the Editor, In a recent publication by Workman et al., 1 the authors examine spread of fluorescent particles during a range of endonasal procedures using a cadaver model and propose guidance on risk of aerosolization with these procedures. This study was designed to measure droplet spread, not aerosol deposition or settling. Infectious aerosols are defined as particles under 100 µm in diameter that are suspended in a gas and can be respired. 2,3 Aerosol particles between 10 and 100 µm tend to deposit in the upper airway whereas particles under 5 to 10 µm in size are the airborne particles that can bypass the upper airway and penetrate deep into the lungs. 2,4,5 Aerosol movement, deposition, and surface settling times are generally influenced by air flow rates in the local environment. 2,4 Simulation of aerosol movement in an exam room demonstrated that aerosol can spread throughout the room within 5 minutes and aerosol clearance is highly dependent on the number of air changes per hour. 6 These fundamental properties of aerosols together with characteristic spread patterns for droplets form the basis for guidelines for personal protective equipment (PPE) use for airborne vs droplet precautions. 3 Workman et al. 1 used an atomizer to create a fluorescent layer of particles ranging in size from 30 to 100 µm in diameter. However, the particles produced during the simulation of aerosol generation by the atomizer alone and during the endoscopic procedures are not limited to this size. The fluorescent particles can attach to other larger particles through hydrostatic forces, including moisture inside the cadaver, or random-sized particles generated by the described endoscopic procedures. These aggregate particles are then expelled from the nose as droplets based on the velocity of the initial spray or net velocity of air movement generated by the endoscopic procedure. This is supported by the results of Figure 3A in Workman et al. 1 In Figure 3A, the size of particles detected outside the model system after expulsion of fluorescent particles generated by the atomizer are in the range of hundreds of microns to about 1500 µm in size, well outside the defined range of infectious aerosols,

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Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis

Cited by 62 publications

References 41 publications

Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1–7

Abrogation of ER stress-induced apoptosis of alveolar epithelial cells by angiotensin 1–7

A Human Long Non-Coding RNA ALT1 Controls the Cell Cycle of Vascular Endothelial Cells Via ACE2 and Cyclin D1 Pathway

Aerosol or droplet: critical definitions in the COVID‐19 era

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