The effect of structural motifs on the ectodomain shedding of human angiotensin-converting enzyme

Conrad, Nailah; Schwager, S.L.U.; Carmona, Adriana K.; Sturrock, Edward D.

doi:10.1016/j.bbrc.2016.10.155

Cited by 7 publications

(5 citation statements)

References 27 publications

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“…Moreover, N-glycosylation is a highly regulated and critical step in the process of transmembrane glycoprotein maturation [22]. TM, a nucleoside antibiotic, was a first step in inhibiting the biosynthesis of N-oligosaccharides in cells which resulting in glycoprotein folding and causing the aggregation of the wrong or unfolded glycoprotein on the endoplasmic reticulum, and finally leaded to ER stress [23] [24]. The previous study has shown that TM enhanced the sensitivity of lung cancer cells [25].…”

Section: Discussionmentioning

confidence: 99%

Effects of Endoplasmic Reticulum Stress on Pulmonary Hypertension in Rat Induced by Chronic Hypoxia and Hypercapnia

Zhang¹,

Zhang²,

Wu³

et al. 2018

JBM

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Objective: To observe the pulmonary vascular remodeling in rats with pulmonary hypertension induced by hypoxia and hypercapnia, and to explore the role of endoplasmic reticulum stress in pulmonary hypertension. Methods: 1) 40 SD rats were randomly divided into four groups: normoxic control group (N), hypoxia hypercapnia group (HH), endoplasmic reticulum stress (ERS) inhibitor 4-phenyl butyric acid group (4-PBA), ERS pathway agonist tunicamycin group (TM). 2) The mean pulmonary arterial pressure (mPAP) and the right ventricular hypertrophy index (RV/(LV + S)) were measured in each group. 3) Identification of pulmonary artery smooth muscle cells (PASMCs) in each group by immunofluorescence α-SMA. 4) Morphological changes of lung tissue and pulmonary artery were observed by electron microscope. 5) The apoptotic index of PASMCs in each group was detected by TUNEL. 6) Reverse transcription polymerase chain reaction (RT-PCR) and Western Blot (WB) were used to detect the expression of ERS related protein and mRNA (GRP78, CHOP, JNK, Caspase-12) in each group. Results: 1) Compared with the N group, the mPAP, RV/(LV + S) and vascular wall area (WA)/total area (TA) value of HH group, 4-PBA group and TM group were increased (P < 0.01), and the vascular lumen area (LA)/TA values, PASMCs apoptosis index were significantly decreased. GRP78, CHOP, JNK, Caspase-12 expression were increased, and the differences were statistically significant. 2) Compared with the HH group, the mPAP, RV/(LV + S) and WA/TA of 4-PBA group were decreased (P < 0.01); the LA/TA value and PASMCs apoptosis index were increased (P < 0.05); and the mRNA and protein expression of CHOP, JNK, Caspase-12 and GRP78 had a significant decrease (P < 0.05). 3) Compared with the HH, the mPAP, RV/(LV + S) and WA/TA of TM group were increased (P < 0.05, P < 0.01), while LA/TA were decreased (P < 0.01); and PASMCs apoptotic index was increased (P < 0.01). Meanwhile, the mRNA expression of Caspase-12, CHOP, JNK and GRP78 was increased to varying degrees (P < 0.05), and the protein expression of Caspase-12, CHOP and JNK was also increased significantly (P < 0.01). Conclusion: Hypoxia and hypercapnia induced pulmonary vascular remodeling may be related to the proliferation of PASMCs, and ERS related factors (JNK, Caspase12 and CHOP) are involved in the regulation of hypoxic hypercapnia.

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Section: Discussionmentioning

confidence: 99%

Effects of Endoplasmic Reticulum Stress on Pulmonary Hypertension in Rat Induced by Chronic Hypoxia and Hypercapnia

Zhang¹,

Zhang²,

Wu³

et al. 2018

JBM

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“…732 (Riordan, 2003) Active site 2 1 Schematic Extracellular domain is in white, transmembrane domain is in blue, and carboxy-terminal cytosolic domain is in orange N-terminal sACE does not have the first 36 residues of N-sequence of tACE (Conrad et al, 2016) C-terminal Human tACE and sACE have the same carboxy-terminal transmembrane and cytosolic sequences (Riordan, 2003) Association with cell membrane Bound to plasma membranes by its C-terminal hydrophobic transmembrane anchor (Coates, 2003) Specific substrate…”

Section: Classification Of Acementioning

confidence: 99%

“…Each of the homologous domains contains a catalytically active site in the middle, which is characterized by a consensus zinc‐binding motif—HEXXH, where X can be any amino acid (Table 1) (Coates, 2003; Deddish et al., 1994; Riordan, 2003). tACE is a membrane‐bound glycoprotein of 732 amino acids with the same cytosolic and transmembrane domains and the same extracellular domain as sACE except for its first 36 residues of the N‐terminal (Conrad, Schwager, Carmona, & Sturrock, 2016; Woodman et al., 2005). The substrate preference of tACE is still unknown and this isoenzyme does not generate angiotensin II in vivo (Atanassova et al., 2009; Corradi, Schwager, Nchinda, Sturrock, & Acharya, 2006).…”

Section: Classification Structure Function and Inhibition Of Acementioning

confidence: 99%

“…The substrate preference of tACE is still unknown and this isoenzyme does not generate angiotensin II in vivo (Atanassova et al, 2009;Corradi, Schwager, Nchinda, Sturrock, & Acharya, 2006). sACE is used as the model ACE in nearly all studies of ACE-inhibitory peptides as it regulates blood pressure TA B L E 1 Similarities and differences between somatic (sACE) and testicular (tACE) angiotensin converting enzyme sACE tACE Location Distributed in all tissues of the body, especially endothelial cells of lung, kidney, small intestine, and epididymis Only in spermatids and spermatozoa, Testosterone-dependent (Riordan, 2003) Number of amino acids 1,306 732 (Riordan, 2003) Active site 2 1 Schematic Extracellular domain is in white, transmembrane domain is in blue, and carboxy-terminal cytosolic domain is in orange N-terminal sACE does not have the first 36 residues of N-sequence of tACE (Conrad et al, 2016) C-terminal Human tACE and sACE have the same carboxy-terminal transmembrane and cytosolic sequences (Riordan, 2003) Association with cell membrane Bound to plasma membranes by its C-terminal hydrophobic transmembrane anchor (Coates, 2003) Specific substrate…”

Section: Classification Of Acementioning

confidence: 99%

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Activity and bioavailability of food protein‐derived angiotensin‐I‐converting enzyme–inhibitory peptides

Xue

Yin

Howell

et al. 2021

Comp Rev Food Sci Food Safe

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Angiotensin‐I‐converting enzyme (ACE) inhibitory peptides are able to inhibit the activity of ACE, which is the key enzymatic factor mediating systemic hypertension. ACE‐inhibitory peptides can be obtained from edible proteins and have the function of antihypertension. The amino acid sequences and the secondary structures of ACE‐inhibitory peptides determine the inhibitory activities and stability. The resistance of ACE‐inhibitory peptides to digestive enzymes and peptidase affect their antihypertensive bioactivity in vivo. In this paper, the mechanism of ACE‐inhibition, sources of the inhibitory peptides, structure–activity relationships, stability during digestion, absorption and transportation of ACE‐inhibitory peptides, and consumption of ACE‐inhibitory peptides are reviewed, which provide guidance to the development of new functional foods and production of antihypertensive nutraceuticals and pharmaceuticals.

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“…Beside undergoing post-translational modifications by glycosylation and phosphorylation, ACE2 is also posttranslationally regulated by shedding from cell membrane through the action of the metalloproteinase ADAM17. The proteolysis of ACE2 releases a soluble, enzymatically active form which corresponds to the ACE2 ectodomain (Jia et al, 2009;Xiao et al, 2014;Conrad et al, 2016). The function, if any, of soluble ACE2 is still obscure, but the shedding mechanism is under strict molecular control.…”

Section: Transcriptional Post-transcriptional and Post-translationamentioning

confidence: 99%

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

Saponaro

Rutigliano

Sestito

et al. 2020

Front. Mol. Biosci.

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Angiotensin-converting enzyme 2 (ACE2) is related to ACE but turned out to counteract several pathophysiological actions of ACE. ACE2 exerts antihypertensive and cardioprotective effects and reduces lung inflammation. ACE2 is subjected to extensive transcriptional and post-transcriptional modulation by epigenetic mechanisms and microRNAs. Also, ACE2 expression is regulated post-translationally by glycosylation, phosphorylation, and shedding from the plasma membrane. ACE2 protein is ubiquitous across mammalian tissues, prominently in the cardiovascular system, kidney, and intestine. ACE2 expression in the respiratory tract is of particular interest, in light of the discovery that ACE2 serves as the initial cellular target of severe acute respiratory syndrome (SARS)-coronaviruses, including the recent SARS-CoV2, responsible of the COronaVIrus Disease 2019 (COVID-19). Since the onset of the COVID-19 pandemic, an intense effort has been made to elucidate the biochemical determinants of SARS-CoV2-ACE2 interaction. It has been determined that SARS-CoV2 engages with ACE2 through its spike (S) protein, which consists of two subunits: S1, that mediates binding to the host receptor; S2, that induces fusion of the viral envelope with the host cell membrane and delivery of the viral genome. Owing to the role of ACE2 in SARS-CoV2 pathogenicity, it has been speculated that medical conditions, i.e., hypertension, and/or drugs, i.e., ACE inhibitors and angiotensin receptor blockers, known to influence ACE2 density could alter the fate of SARS-CoV-2 infection. The debate is still open and will only be solved when results of properly designed experimental and clinical investigations will be made public. An interesting observation is, however that, upon infection, ACE2 activity is reduced either by downregulation or by shedding. These events might precipitate the so-called "cytokine storm" that characterizes the most severe COVID-19 forms. As evidence accumulates, ACE2 appears a druggable target in the attempt to limit virus entry and replication. Strategies aimed at blocking ACE2 with antibodies, small molecules or peptides, or at neutralizing the virus by competitive binding with exogenously administered ACE2, are currently under investigations. In this review, we will present an overview of the state-of-the-art knowledge on ACE2 biochemistry and pathophysiology, outlining open issues in the context of COVID-19 disease and potential experimental and clinical developments.

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The effect of structural motifs on the ectodomain shedding of human angiotensin-converting enzyme

Cited by 7 publications

References 27 publications

Effects of Endoplasmic Reticulum Stress on Pulmonary Hypertension in Rat Induced by Chronic Hypoxia and Hypercapnia

Effects of Endoplasmic Reticulum Stress on Pulmonary Hypertension in Rat Induced by Chronic Hypoxia and Hypercapnia

Activity and bioavailability of food protein‐derived angiotensin‐I‐converting enzyme–inhibitory peptides

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives

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