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Li X, Ding H, Feng G, Huang Y. Role of angiotensin converting enzyme in pathogenesis associated with immunity in cardiovascular diseases. Life Sci 2024; 352:122903. [PMID: 38986897 DOI: 10.1016/j.lfs.2024.122903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 06/18/2024] [Accepted: 07/06/2024] [Indexed: 07/12/2024]
Abstract
Angiotensin converting enzyme (ACE) is not only a critical component in the renin-angiotensin system (RAS), but also suggested as an important mediator for immune response and activity, such as immune cell mobilization, metabolism, biogenesis of immunoregulatory molecules, etc. The chronic duration of cardiovascular diseases (CVD) has been increasingly considered to be triggered by uncontrolled pathologic immune reactions from myeloid cells and lymphocytes. Considering the potential anti-inflammatory effect of the traditional antihypertensive ACE inhibitor (ACEi), we attempt to elucidate whether ACE and its catalytically relevant substances as well as signaling pathways play a role in the immunity-related pathogenesis of common CVD, such as arterial hypertension, atherosclerosis and arrythmias. ACEi was also reported to benefit the prognoses of COVID-19-positive patients with CVD, and COVID-19 disease with preexisting CVD or subsequent cardiovascular damage is featured by a significant influx of immune cells and proinflammatory molecules, suggesting that ACE may also participate in COVID-19 induced cardiovascular injury, because COVID-19 disease basically triggers an overactive pathologic immune response. Hopefully, the ACE inhibition and manipulation of those associated bioactive signals could supplement the current medicinal management of various CVD and bring greater benefit to patients' cardiovascular health.
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Affiliation(s)
- Xinyi Li
- Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Huasheng Ding
- Department of Emergency, Shenzhen Hospital, Southern Medical University, Shenzhen, China
| | - Gaoke Feng
- Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China
| | - Yan Huang
- Department of Cardiology and Cardiovascular Research Institute, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Hubei Key Laboratory of Cardiology, Wuhan, Hubei, China.
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2
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Acharya K, Gregory K, Sturrock E. Advances in the structural basis for angiotensin-1 converting enzyme (ACE) inhibitors. Biosci Rep 2024; 44:BSR20240130. [PMID: 39046229 PMCID: PMC11300679 DOI: 10.1042/bsr20240130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/24/2024] [Accepted: 07/24/2024] [Indexed: 07/25/2024] Open
Abstract
Human somatic angiotensin-converting enzyme (ACE) is a key zinc metallopeptidase that plays a pivotal role in the renin-angiotensin-aldosterone system (RAAS) by regulating blood pressure and electrolyte balance. Inhibition of ACE is a cornerstone in the management of hypertension, cardiovascular diseases, and renal disorders. Recent advances in structural biology techniques have provided invaluable insights into the molecular mechanisms underlying ACE inhibition, facilitating the design and development of more effective therapeutic agents. This review focuses on the latest advancements in elucidating the structural basis for ACE inhibition. High-resolution crystallographic studies of minimally glycosylated individual domains of ACE have revealed intricate molecular details of the ACE catalytic N- and C-domains, and their detailed interactions with clinically relevant and newly designed domain-specific inhibitors. In addition, the recently elucidated structure of the glycosylated form of full-length ACE by cryo-electron microscopy (cryo-EM) has shed light on the mechanism of ACE dimerization and revealed continuous conformational changes which occur prior to ligand binding. In addition to these experimental techniques, computational approaches have also played a pivotal role in elucidating the structural basis for ACE inhibition. Molecular dynamics simulations and computational docking studies have provided atomic details of inhibitor binding kinetics and energetics, facilitating the rational design of novel ACE inhibitors with improved potency and selectivity. Furthermore, computational analysis of the motions observed by cryo-EM allowed the identification of allosteric binding sites on ACE. This affords new opportunities for the development of next-generation allosteric inhibitors with enhanced pharmacological properties. Overall, the insights highlighted in this review could enable the rational design of novel ACE inhibitors with improved efficacy and safety profiles, ultimately leading to better therapeutic outcomes for patients with hypertension and cardiovascular diseases.
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Affiliation(s)
- K. Ravi Acharya
- Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, U.K
| | - Kyle S. Gregory
- Department of Life Sciences, University of Bath, Claverton Down, Bath BA2 7AY, U.K
| | - Edward D. Sturrock
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Cape Town, Republic of South Africa
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3
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Żukowska J, Moss SJ, Subramanian V, Acharya KR. Molecular basis of selective amyloid-β degrading enzymes in Alzheimer's disease. FEBS J 2024; 291:2999-3029. [PMID: 37622248 DOI: 10.1111/febs.16939] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 07/31/2023] [Accepted: 08/22/2023] [Indexed: 08/26/2023]
Abstract
The accumulation of the small 42-residue long peptide amyloid-β (Aβ) has been proposed as a major trigger for the development of Alzheimer's disease (AD). Within the brain, the concentration of Aβ peptide is tightly controlled through production and clearance mechanisms. Substantial experimental evidence now shows that reduced levels of Aβ clearance are present in individuals living with AD. This accumulation of Aβ can lead to the formation of large aggregated amyloid plaques-one of two detectable hallmarks of the disease. Aβ-degrading enzymes (ADEs) are major players in the clearance of Aβ. Stimulating ADE activity or expression, in order to compensate for the decreased clearance in the AD phenotype, provides a promising therapeutic target. It has been reported in mice that upregulation of ADEs can reduce the levels of Aβ peptide and amyloid plaques-in some cases, this led to improved cognitive function. Among several known ADEs, neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), insulin degrading enzyme (IDE) and angiotensin-1 converting enzyme (ACE) from the zinc metalloprotease family have been identified as important. These ADEs have the capacity to digest soluble Aβ which, in turn, cannot form the toxic oligomeric species. While they are known for their amyloid degradation, they exhibit complexity through promiscuous nature and a broad range of substrates that they can degrade. This review highlights current structural and functional understanding of these key ADEs, giving some insight into the molecular interactions that leads to the hydrolysis of peptide substrates, the crucial tasks performed by them and the potential for therapeutic use in the future.
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4
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Oosthuizen D, Ganief TA, Bernstein KE, Sturrock ED. Proteomic Analysis of Human Macrophages Overexpressing Angiotensin-Converting Enzyme. Int J Mol Sci 2024; 25:7055. [PMID: 39000163 PMCID: PMC11240931 DOI: 10.3390/ijms25137055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/21/2024] [Accepted: 06/23/2024] [Indexed: 07/16/2024] Open
Abstract
Angiotensin converting enzyme (ACE) exerts strong modulation of myeloid cell function independently of its cardiovascular arm. The success of the ACE-overexpressing murine macrophage model, ACE 10/10, in treating microbial infections and cancer opens a new avenue into whether ACE overexpression in human macrophages shares these benefits. Additionally, as ACE inhibitors are a widely used antihypertensive medication, their impact on ACE expressing immune cells is of interest and currently understudied. In the present study, we utilized mass spectrometry to characterize and assess global proteomic changes in an ACE-overexpressing human THP-1 cell line. Additionally, proteomic changes and cellular uptake following treatment with an ACE C-domain selective inhibitor, lisinopril-tryptophan, were also assessed. ACE activity was significantly reduced following inhibitor treatment, despite limited uptake within the cell, and both RNA processing and immune pathways were significantly dysregulated with treatment. Also present were upregulated energy and TCA cycle proteins and dysregulated cytokine and interleukin signaling proteins with ACE overexpression. A novel, functionally enriched immune pathway that appeared both with ACE overexpression and inhibitor treatment was neutrophil degranulation. ACE overexpression within human macrophages showed similarities with ACE 10/10 murine macrophages, paving the way for mechanistic studies aimed at understanding the altered immune function.
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Affiliation(s)
- Delia Oosthuizen
- Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa
| | - Tariq A. Ganief
- Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa
| | - Kenneth E. Bernstein
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA
| | - Edward D. Sturrock
- Division of Chemical, Systems and Synthetic Biology, Faculty of Health Sciences, Institute for Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa
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5
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Lubbe L, Sewell BT, Woodward JD, Sturrock ED. Cryo-EM reveals mechanisms of angiotensin I-converting enzyme allostery and dimerization. EMBO J 2022; 41:e110550. [PMID: 35818993 PMCID: PMC9379546 DOI: 10.15252/embj.2021110550] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 04/21/2022] [Accepted: 05/27/2022] [Indexed: 11/09/2022] Open
Abstract
Hypertension (high blood pressure) is a major risk factor for cardiovascular disease, which is the leading cause of death worldwide. The somatic isoform of angiotensin I‐converting enzyme (sACE) plays a critical role in blood pressure regulation, and ACE inhibitors are thus widely used to treat hypertension and cardiovascular disease. Our current understanding of sACE structure, dynamics, function, and inhibition has been limited because truncated, minimally glycosylated forms of sACE are typically used for X‐ray crystallography and molecular dynamics simulations. Here, we report the first cryo‐EM structures of full‐length, glycosylated, soluble sACE (sACES1211). Both monomeric and dimeric forms of the highly flexible apo enzyme were reconstructed from a single dataset. The N‐ and C‐terminal domains of monomeric sACES1211 were resolved at 3.7 and 4.1 Å, respectively, while the interacting N‐terminal domains responsible for dimer formation were resolved at 3.8 Å. Mechanisms are proposed for intradomain hinging, cooperativity, and homodimerization. Furthermore, the observation that both domains were in the open conformation has implications for the design of sACE modulators.
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Affiliation(s)
- Lizelle Lubbe
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
| | - Bryan Trevor Sewell
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.,Electron Microscope Unit, University of Cape Town, Cape Town, South Africa
| | - Jeremy D Woodward
- Electron Microscope Unit, University of Cape Town, Cape Town, South Africa
| | - Edward D Sturrock
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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6
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Polymorphisms in common antihypertensive targets: Pharmacogenomic implications for the treatment of cardiovascular disease. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 94:141-182. [PMID: 35659371 DOI: 10.1016/bs.apha.2022.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The idea of personalized medicine came to fruition with sequencing the human genome; however, aside from a few cases, the genetic revolution has yet to materialize. Cardiovascular diseases are the leading cause of death globally, and hypertension is a common prelude to nearly all cardiovascular diseases. Thus, hypertension is an ideal candidate disease to apply tenants of personalized medicine to lessen cardiovascular disease. Herein is a survey that visually depicts the polymorphisms in the top eight antihypertensive targets. Although there are numerous genome-wide association studies regarding cardiovascular disease, few studies look at the effects of receptor polymorphisms on drug treatment. With 17,000+ polymorphisms in the combined target proteins examined, it is expected that some of the clinical variability in the treatment of hypertension is due to polymorphisms in the drug targets. Recent advances in techniques and technology, such as high throughput examination of single mutations, structure prediction, computational power for modeling, and CRISPR models of point mutations, allow for a relatively rapid and comprehensive examination of the effects of known and future polymorphisms on drug affinity and effects. As hypertension is easy to measure and has a plethora of clinically viable ligands, hypertension makes an excellent disease to study pharmacogenomics in the lab and the clinic. If the promises of personalized medicine are to materialize, a concerted effort to examine the effects polymorphisms have on drugs is required. A clinician with the knowledge of a patient's genotype can then prescribe drugs that are optimal for treating that specific patient.
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7
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Ratajczak MZ, Bujko K, Ciechanowicz A, Sielatycka K, Cymer M, Marlicz W, Kucia M. SARS-CoV-2 Entry Receptor ACE2 Is Expressed on Very Small CD45 - Precursors of Hematopoietic and Endothelial Cells and in Response to Virus Spike Protein Activates the Nlrp3 Inflammasome. Stem Cell Rev Rep 2021; 17:266-277. [PMID: 32691370 PMCID: PMC7370872 DOI: 10.1007/s12015-020-10010-z] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Angiotensin-converting enzyme 2 (ACE2) plays an important role as a member of the renin-angiotensin-aldosterone system (RAAS) in regulating the conversion of angiotensin II (Ang II) into angiotensin (1-7) (Ang [1-7]). But at the same time, while expressed on the surface of human cells, ACE2 is the entry receptor for SARS-CoV-2. Expression of this receptor has been described in several types of cells, including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), which raises a concern that the virus may infect and damage the stem cell compartment. We demonstrate for the first time that ACE2 and the entry-facilitating transmembrane protease TMPRSS2 are expressed on very small CD133+CD34+Lin-CD45- cells in human umbilical cord blood (UCB), which can be specified into functional HSCs and EPCs. The existence of these cells known as very small embryonic-like stem cells (VSELs) has been confirmed by several laboratories, and some of them may correspond to putative postnatal hemangioblasts. Moreover, we demonstrate for the first time that, in human VSELs and HSCs, the interaction of the ACE2 receptor with the SARS-CoV-2 spike protein activates the Nlrp3 inflammasome, which if hyperactivated may lead to cell death by pyroptosis. Based on this finding, there is a possibility that human VSELs residing in adult tissues could be damaged by SARS-CoV-2, with remote effects on tissue/organ regeneration. We also report that ACE2 is expressed on the surface of murine bone marrow-derived VSELs and HSCs, although it is known that murine cells are not infected by SARS-CoV-2. Finally, human and murine VSELs express several RAAS genes, which sheds new light on the role of these genes in the specification of early-development stem cells. Graphical Abstract •Human VSELs and HSCs express ACE2 receptor for SARS-CoV2 entry. •Interaction of viral spike protein with ACE2 receptor may hyperactivate Nlrp3 inflammasome which induces cell death by pyroptosis. •SARS-CoV2 may also enter cells and eliminate them by cell lysis. •What is not shown since these cells express also Ang II receptor they may hyperactivate Nlrp3 inflammasome in response to Ang II which may induce pyroptosis. Our data indicates that Ang 1-7 may have a protective effect.
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Affiliation(s)
- Mariusz Z. Ratajczak
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Kamila Bujko
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
| | - Andrzej Ciechanowicz
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Kasia Sielatycka
- Institute of Biology, Faculty of Exact and Natural Sciences, University of Szczecin, Szczecin, Poland
- Research and Developmental Center Sanprobi, Szczecin, Poland
| | - Monika Cymer
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | | | - Magda Kucia
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY 40202 USA
- Department of Regenerative Medicine, Center for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
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8
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Mohammad A, Marafie SK, Alshawaf E, Abu-Farha M, Abubaker J, Al-Mulla F. Structural analysis of ACE2 variant N720D demonstrates a higher binding affinity to TMPRSS2. Life Sci 2020; 259:118219. [PMID: 32768580 PMCID: PMC7405906 DOI: 10.1016/j.lfs.2020.118219] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/29/2020] [Accepted: 08/03/2020] [Indexed: 12/13/2022]
Abstract
Aims Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel member of the betacoronaviruses family affecting the lower respiratory tract mainly through binding to angiotensin converting enzyme 2 (ACE2) via its S-protein. Genetic analysis of (ACE2) gene revealed several variants that have been suggested to regulate the interaction with S protein. This study investigates the N720D variant, positioned in the collectrin-like domain (CLD) at proximity to type II transmembrane serine protease (TMPRSS2) cleavage site. Main methods The effect of N720D variant on ACE2 structure and thermodynamic stability was studied by DynaMut. HDOCK was utilised to model TMPRSS2 protease binding to ACE2 WT and D720 variant cleavage site. PRODIGY was used to calculate binding affinities and MD simulation tools calculated the at 100 ns for ACE2 apo structure and the ACE2-TMPRSS2 complex. Key findings The N720D variant is a more dynamic structure with a free energy change (ΔΔG): −0.470 kcal/mol. As such, introducing a tighter binding affinity of Kd = 3.2 × 10−10 M between TMPRSS2 and N720D variant. RMSD, RMSF calculations showed the N720D variant is less stable, however, RMSF values of the D720-TMPRSS2 complex reflected a slower dynamic motion. Significance The hotspot N720D variant in the CLD of ACE2 affected the stability and flexibility of ACE2 by increasing the level of motion in the loop region, resulting in a more favourable site for TMPRSS2 binding and cleavage. Consequently, this would facilitate S-protein binding and can potentially increase viral entry highlighting the importance of variants affecting the ACE2-TMPRSS2 complex.
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Affiliation(s)
- Anwar Mohammad
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait.
| | - Sulaiman K Marafie
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait
| | - Eman Alshawaf
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait
| | - Mohamed Abu-Farha
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait
| | - Jehad Abubaker
- Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Kuwait.
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9
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Alhenc-Gelas F, Bouby N, Girolami JP. Kallikrein/K1, Kinins, and ACE/Kininase II in Homeostasis and in Disease Insight From Human and Experimental Genetic Studies, Therapeutic Implication. Front Med (Lausanne) 2019; 6:136. [PMID: 31316987 PMCID: PMC6610447 DOI: 10.3389/fmed.2019.00136] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 05/31/2019] [Indexed: 01/19/2023] Open
Abstract
Kallikrein-K1 is the main kinin-forming enzyme in organs in resting condition and in several pathological situations whereas angiotensin I-converting enzyme/kininase II (ACE) is the main kinin-inactivating enzyme in the circulation. Both ACE and K1 activity levels are genetic traits in man. Recent research based mainly on human genetic studies and study of genetically modified mice has documented the physiological role of K1 in the circulation, and also refined understanding of the role of ACE. Kallikrein-K1 is synthesized in arteries and involved in flow-induced vasodilatation. Endothelial ACE synthesis displays strong vessel and organ specificity modulating bioavailability of angiotensins and kinins locally. In pathological situations resulting from hemodynamic, ischemic, or metabolic insult to the cardiovascular system and the kidney K1 and kinins exert critical end-organ protective action and K1 deficiency results in severe worsening of the conditions, at least in the mouse. On the opposite, genetically high ACE level is associated with increased risk of developing ischemic and diabetic cardiac or renal diseases and worsened prognosis of these diseases. The association has been well-documented clinically while causality was established by ACE gene titration in mice. Studies suggest that reduced bioavailability of kinins is prominently involved in the detrimental effect of K1 deficiency or high ACE activity in diseases. Kinins are involved in the therapeutic effect of both ACE inhibitors and angiotensin II AT1 receptor blockers. Based on these findings, a new therapeutic hypothesis focused on selective pharmacological activation of kinin receptors has been launched. Proof of concept was obtained by using prototypic agonists in experimental ischemic and diabetic diseases in mice.
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Affiliation(s)
- Francois Alhenc-Gelas
- INSERM U1138-CRC, Paris, France.,CRC-INSERM U1138, Paris-Descartes University, Paris, France.,CRC-INSERM U1138, Sorbonne University, Paris, France
| | - Nadine Bouby
- INSERM U1138-CRC, Paris, France.,CRC-INSERM U1138, Paris-Descartes University, Paris, France.,CRC-INSERM U1138, Sorbonne University, Paris, France
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10
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Lubbe L, Sturrock ED. Interacting cogs in the machinery of the renin angiotensin system. Biophys Rev 2019; 11:583-589. [PMID: 31177382 PMCID: PMC6682192 DOI: 10.1007/s12551-019-00555-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 05/29/2019] [Indexed: 01/19/2023] Open
Abstract
Somatic angiotensin converting enzyme (sACE) is well-known for its role in blood pressure regulation and consequently, ACE inhibitors are widely prescribed for the treatment of hypertension. More than 60 years after the discovery of sACE, however, the molecular details of its substrate hydrolysis and inhibition are still poorly understood. Isothermal titration calorimetry, molecular dynamics simulations and fine epitope mapping suggest that substrate or inhibitor binding triggers a hinging motion between the two subdomains of each domain. Ligand binding to one domain further induces a conformational change in sACE to negatively affect the second domain's function and can also cause dimerization between sACE molecules. This has been linked to an increase in sACE expression via intracellular signalling. Inhibitor-induced dimerization could thus decrease the efficacy of hypertension treatment. At present, the only structural information available for sACE are crystal structures of the truncated domains in the closed conformation due to the presence of ligands. These structures do not provide any information regarding the open active site conformation prior to ligand binding, the relative orientation of the two domains in full-length sACE, or the dimerization interface. To guarantee effective therapeutic intervention, further research is required to investigate the hinging, negative cooperativity and dimerization of sACE. This review describes our current understanding of these interactions and proposes how recent advances in cryo-electron microscopy could enable structural elucidation of their mechanisms.
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Affiliation(s)
- Lizelle Lubbe
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa
| | - Edward D Sturrock
- Department of Integrative Biomedical Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa.
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11
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Abrie JA, Moolman WJA, Cozier GE, Schwager SL, Acharya KR, Sturrock ED. Investigation into the Mechanism of Homo- and Heterodimerization of Angiotensin-Converting Enzyme. Mol Pharmacol 2018; 93:344-354. [PMID: 29371233 DOI: 10.1124/mol.117.110866] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 01/19/2018] [Indexed: 11/22/2022] Open
Abstract
Angiotensin-converting enzyme (ACE) plays a central role in the renin-angiotensin system (RAS), which is primarily responsible for blood pressure homeostasis. Studies have shown that ACE inhibitors yield cardiovascular benefits that cannot be entirely attributed to the inhibition of ACE catalytic activity. It is possible that these benefits are due to interactions between ACE and RAS receptors that mediate the protective arm of the RAS, such as angiotensin II receptor type 2 (AT2R) and the receptor MAS. Therefore, in this study, we investigated the molecular interactions of ACE, including ACE homodimerization and heterodimerization with AT2R and MAS, respectively. Molecular interactions were assessed by fluorescence resonance energy transfer and bimolecular fluorescence complementation in human embryonic kidney 293 cells and Chinese hamster ovary-K1 cells transfected with vectors encoding fluorophore-tagged proteins. The specificity of dimerization was verified by competition experiments using untagged proteins. These techniques were used to study several potential requirements for the germinal isoform of angiotensin-converting enzyme expressed in the testes (tACE) dimerization as well as the effect of ACE inhibitors on both somatic isoforms of angiotensin-converting enzyme expressed in the testes (sACE) and tACE dimerization. We demonstrated constitutive homodimerization of sACE and of both of its domains separately, as well as heterodimerization of both sACE and tACE with AT2R, but not MAS. In addition, we investigated both soluble sACE and the sACE N domain using size-exclusion chromatography-coupled small-angle X-ray scattering and we observed dimers in solution for both forms of the enzyme. Our results suggest that ACE homo- and heterodimerization does occur under physiologic conditions.
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Affiliation(s)
- J Albert Abrie
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa (J.A.A., W.J.A.M., S.L.S., E.D.S.); and Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom (G.E.C., K.R.A.)
| | - Wessel J A Moolman
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa (J.A.A., W.J.A.M., S.L.S., E.D.S.); and Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom (G.E.C., K.R.A.)
| | - Gyles E Cozier
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa (J.A.A., W.J.A.M., S.L.S., E.D.S.); and Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom (G.E.C., K.R.A.)
| | - Sylva L Schwager
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa (J.A.A., W.J.A.M., S.L.S., E.D.S.); and Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom (G.E.C., K.R.A.)
| | - K Ravi Acharya
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa (J.A.A., W.J.A.M., S.L.S., E.D.S.); and Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom (G.E.C., K.R.A.)
| | - Edward D Sturrock
- Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa (J.A.A., W.J.A.M., S.L.S., E.D.S.); and Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom (G.E.C., K.R.A.)
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12
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Kohlstedt K, Trouvain C, Frömel T, Mudersbach T, Henschler R, Fleming I. Role of the angiotensin-converting enzyme in the G-CSF-induced mobilization of progenitor cells. Basic Res Cardiol 2018; 113:18. [PMID: 29549541 DOI: 10.1007/s00395-018-0677-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 03/15/2018] [Indexed: 12/22/2022]
Abstract
In addition to being a peptidase, the angiotensin-converting enzyme (ACE) can be phosphorylated and involved in signal transduction. We evaluated the role of ACE in granulocyte-colony-stimulating factor (G-CSF)-induced hematopoietic progenitor cell (HPC) mobilization and detected a significant increase in mice-lacking ACE. Transplantation experiments revealed that the loss of ACE in the HPC microenvironment rather than in the HPCs increased mobilization. Indeed, although ACE was expressed by a small population of bone-marrow cells, it was more strongly expressed by endosteal bone. Interestingly, there was a physical association of ACE with the G-CSF receptor (CD114), and G-CSF elicited ACE phosphorylation on Ser1270 in vivo and in vitro. A transgenic mouse expressing a non-phosphorylatable ACE (ACES/A) mutant demonstrated increased G-CSF-induced HPC mobilization and decreased G-CSF-induced phosphorylation of STAT3 and STAT5. These results indicate that ACE expression/phosphorylation in the bone-marrow niche interface negatively regulates G-CSF-induced signaling and HPC mobilization.
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Affiliation(s)
- Karin Kohlstedt
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.,German Centre for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Frankfurt am Main, Germany
| | - Caroline Trouvain
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Timo Frömel
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.,German Centre for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Frankfurt am Main, Germany
| | - Thomas Mudersbach
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.,German Centre for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Frankfurt am Main, Germany
| | - Reinhard Henschler
- Blood Donor Services Zürich and Chur, Swiss Red Cross, Zurich, Switzerland
| | - Ingrid Fleming
- Institute for Vascular Signalling, Centre for Molecular Medicine, Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany. .,German Centre for Cardiovascular Research (DZHK), Partner Site Rhein-Main, Frankfurt am Main, Germany.
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13
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Martinez J. Joseph Rudinger memorial lecture: Unexpected functions of angiotensin converting enzyme, beyond its enzymatic activity. J Pept Sci 2017. [DOI: 10.1002/psc.3022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Jean Martinez
- Institut des Biomolécules Max Mousseron; UMR 5247 CNRS-Université de Montpellier-ENSCM; Faculté de Pharmacie, 15 Avenue Charles Flahault 34093 Montpellier Cedex 5 France
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14
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Danilov SM, Tovsky SI, Schwartz DE, Dull RO. ACE Phenotyping as a Guide Toward Personalized Therapy With ACE Inhibitors. J Cardiovasc Pharmacol Ther 2017; 22:374-386. [DOI: 10.1177/1074248416686188] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Background: Angiotensin-converting enzyme (ACE) inhibitors (ACEI) are widely used in the management of cardiovascular diseases but with significant interindividual variability in the patient’s response. Objectives: To investigate whether interindividual variability in the response to ACE inhibitors is explained by the “ACE phenotype”—for example, variability in plasma ACE concentration, activity, and conformation and/or the degree of ACE inhibition in each individual. Methods: The ACE phenotype was determined in plasma of 14 patients with hypertension treated chronically for 4 weeks with 40 mg enalapril (E) or 20 mg E + 16 mg candesartan (EC) and in 20 patients with hypertension treated acutely with a single dose (20 mg) of E with or without pretreatment with hydrochlorothiazide. The ACE phenotyping included (1) plasma ACE concentration; (2) ACE activity (with 2 substrates: Hip-His-Leu and Z-Phe-His-Leu and calculation of their ratio); (3) detection of ACE inhibitors in patient’s blood (indicator of patient compliance) and the degree of ACE inhibition (ie, adherence); and (4) ACE conformation. Results: Enalapril reduced systolic and diastolic blood pressure in most patients; however, 20% of patients were considered nonresponders. Chronic treatment results in 40% increase in serum ACE concentrations, with the exception of 1 patient. There was a trend toward better response to ACEI among patients who had a higher plasma ACE concentration. Conclusion: Due to the fact that “20% of patients do not respond to ACEI by blood pressure drop,” the initial blood ACE level could not be a predictor of blood pressure reduction in an individual patient. However, ACE phenotyping provides important information about conformational and kinetic changes in ACE of individual patients, and this could be a reason for resistance to ACE inhibitors in some nonresponders.
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Affiliation(s)
- Sergei M. Danilov
- Department of Anesthesiology, Anesthesiology Research Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Stan I. Tovsky
- Department of Anesthesiology, Anesthesiology Research Center, University of Illinois at Chicago, Chicago, IL, USA
| | - David E. Schwartz
- Department of Anesthesiology, Anesthesiology Research Center, University of Illinois at Chicago, Chicago, IL, USA
| | - Randal O. Dull
- Department of Anesthesiology, Anesthesiology Research Center, University of Illinois at Chicago, Chicago, IL, USA
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Aztatzi-Aguilar OG, Uribe-Ramírez M, Arias-Montaño JA, Barbier O, De Vizcaya-Ruiz A. Acute and subchronic exposure to air particulate matter induces expression of angiotensin and bradykinin-related genes in the lungs and heart: Angiotensin-II type-I receptor as a molecular target of particulate matter exposure. Part Fibre Toxicol 2015; 12:17. [PMID: 26113123 PMCID: PMC4482198 DOI: 10.1186/s12989-015-0094-4] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Accepted: 06/15/2015] [Indexed: 01/03/2023] Open
Abstract
Background Particulate matter (PM) adverse effects on health include lung and heart damage. The renin-angiotensin-aldosterone (RAAS) and kallikrein-kinin (KKS) endocrine systems are involved in the pathophysiology of cardiovascular diseases and have been found to impact lung diseases. The aim of the present study was to evaluate whether PM exposure regulates elements of RAAS and KKS. Methods Sprague–Dawley rats were acutely (3 days) and subchronically (8 weeks) exposed to coarse (CP), fine (FP) or ultrafine (UFP) particulates using a particulate concentrator, and a control group exposed to filtered air (FA). We evaluated the mRNA of the RAAS components At1, At2r and Ace, and of the KKS components B1r, B2r and Klk-1 by RT-PCR in the lungs and heart. The ACE and AT1R protein were evaluated by Western blot, as were HO-1 and γGCSc as indicators of the antioxidant response and IL-6 levels as an inflammation marker. We performed a binding assay to determinate AT1R density in the lung, also the subcellular AT1R distribution in the lungs was evaluated. Finally, we performed a histological analysis of intramyocardial coronary arteries and the expression of markers of heart gene reprogramming (Acta1 and Col3a1). Results The PM fractions induced the expression of RAAS and KKS elements in the lungs and heart in a time-dependent manner. CP exposure induced Ace mRNA expression and regulated its protein in the lungs. Acute and subchronic exposure to FP and UFP induced the expression of At1r in the lungs and heart. All PM fractions increased the AT1R protein in a size-dependent manner in the lungs and heart after subchronic exposure. The AT1R lung protein showed a time-dependent change in subcellular distribution. In addition, the presence of AT1R in the heart was accompanied by a decrease in HO-1, which was concomitant with the induction of Acta1 and Col3a1 and the increment of IL-6. Moreover, exposure to all PM fractions increased coronary artery wall thickness. Conclusion We demonstrate that exposure to PM induces the expression of RAAS and KKS elements, including AT1R, which was the main target in the lungs and the heart.
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Affiliation(s)
- Octavio Gamaliel Aztatzi-Aguilar
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional, 2508, México D. F, CP. 07360, Mexico.
| | - Marisela Uribe-Ramírez
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional, 2508, México D. F, CP. 07360, Mexico.
| | - José Antonio Arias-Montaño
- Departamento de Fisiología, Neurociencias y Biofísica, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional, 2508, México D. F, C.P. 07360, Mexico.
| | - Olivier Barbier
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional, 2508, México D. F, CP. 07360, Mexico.
| | - Andrea De Vizcaya-Ruiz
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Avenida Instituto Politécnico Nacional, 2508, México D. F, CP. 07360, Mexico.
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Ferrão FM, Lara LS, Lowe J. Renin-angiotensin system in the kidney: What is new? World J Nephrol 2014; 3:64-76. [PMID: 25332897 PMCID: PMC4202493 DOI: 10.5527/wjn.v3.i3.64] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2014] [Revised: 07/07/2014] [Accepted: 07/29/2014] [Indexed: 02/06/2023] Open
Abstract
The renin-angiotensin system (RAS) has been known for more than a century as a cascade that regulates body fluid balance and blood pressure. Angiotensin II(Ang II) has many functions in different tissues; however it is on the kidney that this peptide exerts its main functions. New enzymes, alternative routes for Ang IIformation or even active Ang II-derived peptides have now been described acting on Ang II AT1 or AT2 receptors, or in receptors which have recently been cloned, such as Mas and AT4. Another interesting observation was that old members of the RAS, such as angiotensin converting enzyme (ACE), renin and prorenin, well known by its enzymatic activity, can also activate intracellular signaling pathways, acting as an outside-in signal transduction molecule or on the renin/(Pro)renin receptor. Moreover, the endocrine RAS, now is also known to have paracrine, autocrine and intracrine action on different tissues, expressing necessary components for local Ang II formation. This in situ formation, especially in the kidney, increases Ang II levels to regulate blood pressure and renal functions. These discoveries, such as the ACE2/Ang-(1-7)/Mas axis and its antangonistic effect rather than classical deleterious Ang II effects, improves the development of new drugs for treating hypertension and cardiovascular diseases.
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17
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Costa M, Ronchi F, Ivanow A, Carmona A, Casarini D, Slocombe R. Association between circulating angiotensin-converting enzyme and exercise-induced pulmonary haemorrhage in Thoroughbred racehorses. Res Vet Sci 2012; 93:993-4. [DOI: 10.1016/j.rvsc.2011.10.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2010] [Revised: 09/29/2011] [Accepted: 10/16/2011] [Indexed: 10/14/2022]
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18
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Chacko AM, Nayak M, Greineder CF, DeLisser HM, Muzykantov VR. Collaborative enhancement of antibody binding to distinct PECAM-1 epitopes modulates endothelial targeting. PLoS One 2012; 7:e34958. [PMID: 22514693 PMCID: PMC3325922 DOI: 10.1371/journal.pone.0034958] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Accepted: 03/08/2012] [Indexed: 12/21/2022] Open
Abstract
Antibodies to platelet endothelial cell adhesion molecule-1 (PECAM-1) facilitate targeted drug delivery to endothelial cells by “vascular immunotargeting.” To define the targeting quantitatively, we investigated the endothelial binding of monoclonal antibodies (mAbs) to extracellular epitopes of PECAM-1. Surprisingly, we have found in human and mouse cell culture models that the endothelial binding of PECAM-directed mAbs and scFv therapeutic fusion protein is increased by co-administration of a paired mAb directed to an adjacent, yet distinct PECAM-1 epitope. This results in significant enhancement of functional activity of a PECAM-1-targeted scFv-thrombomodulin fusion protein generating therapeutic activated Protein C. The “collaborative enhancement” of mAb binding is affirmed in vivo, as manifested by enhanced pulmonary accumulation of intravenously administered radiolabeled PECAM-1 mAb when co-injected with an unlabeled paired mAb in mice. This is the first demonstration of a positive modulatory effect of endothelial binding and vascular immunotargeting provided by the simultaneous binding a paired mAb to adjacent distinct epitopes. The “collaborative enhancement” phenomenon provides a novel paradigm for optimizing the endothelial-targeted delivery of therapeutic agents.
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Affiliation(s)
- Ann-Marie Chacko
- Department of Radiology, Division of Nuclear Medicine and Clinical Molecular Imaging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Madhura Nayak
- Department of Radiology, Division of Nuclear Medicine and Clinical Molecular Imaging, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Colin F. Greineder
- Department of Emergency Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Horace M. DeLisser
- Pulmonary, Allergy & Critical Care Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Vladimir R. Muzykantov
- Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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Angiotensin-converting enzyme 2: the first decade. Int J Hypertens 2011; 2012:307315. [PMID: 22121476 PMCID: PMC3216391 DOI: 10.1155/2012/307315] [Citation(s) in RCA: 162] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2011] [Accepted: 08/25/2011] [Indexed: 12/25/2022] Open
Abstract
The renin-angiotensin system (RAS) is a critical regulator of hypertension, primarily through the actions of the vasoactive peptide Ang II, which is generated by the action of angiotensin-converting enzyme (ACE) mediating an increase in blood pressure. The discovery of ACE2, which primarily metabolises Ang II into the vasodilatory Ang-(1-7), has added a new dimension to the traditional RAS. As a result there has been huge interest in ACE2 over the past decade as a potential therapeutic for lowering blood pressure, especially elevation resulting from excess Ang II. Studies focusing on ACE2 have helped to reveal other actions of Ang-(1-7), outside vasodilation, such as antifibrotic and antiproliferative effects. Moreover, investigations focusing on ACE2 have revealed a variety of roles not just catalytic but also as a viral receptor and amino acid transporter. This paper focuses on what is known about ACE2 and its biological roles, paying particular attention to the regulation of ACE2 expression. In light of the entrance of human recombinant ACE2 into clinical trials, we discuss the potential use of ACE2 as a therapeutic and highlight some pertinent questions that still remain unanswered about ACE2.
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20
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An angiotensin I-converting enzyme mutation (Y465D) causes a dramatic increase in blood ACE via accelerated ACE shedding. PLoS One 2011; 6:e25952. [PMID: 21998728 PMCID: PMC3187827 DOI: 10.1371/journal.pone.0025952] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Accepted: 09/14/2011] [Indexed: 11/23/2022] Open
Abstract
Background Angiotensin I-converting enzyme (ACE) metabolizes a range of peptidic substrates and plays a key role in blood pressure regulation and vascular remodeling. Thus, elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases. Previously, a striking familial elevation in blood ACE was explained by mutations in the ACE juxtamembrane region that enhanced the cleavage-secretion process. Recently, we found a family whose affected members had a 6-fold increase in blood ACE and a Tyr465Asp (Y465D) substitution, distal to the stalk region, in the N domain of ACE. Methodology/Principal Findings HEK and CHO cells expressing mutant (Tyr465Asp) ACE demonstrate a 3- and 8-fold increase, respectively, in the rate of ACE shedding compared to wild-type ACE. Conformational fingerprinting of mutant ACE demonstrated dramatic changes in ACE conformation in several different epitopes of ACE. Cell ELISA carried out on CHO-ACE cells also demonstrated significant changes in local ACE conformation, particularly proximal to the stalk region. However, the cleavage site of the mutant ACE - between Arg1203 and Ser1204 - was the same as that of WT ACE. The Y465D substitution is localized in the interface of the N-domain dimer (from the crystal structure) and abolishes a hydrogen bond between Tyr465 in one monomer and Asp462 in another. Conclusions/Significance The Y465D substitution results in dramatic increase in the rate of ACE shedding and is associated with significant local conformational changes in ACE. These changes could result in increased ACE dimerization and accessibility of the stalk region or the entire sACE, thus increasing the rate of cleavage by the putative ACE secretase (sheddase).
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Abstract
For cancers to develop, sustain and spread, the appropriation of key homeostatic physiological systems that influence cell growth, migration and death, as well as inflammation and the expansion of vascular networks are required. There is accumulating molecular and in vivo evidence to indicate that the expression and actions of the renin-angiotensin system (RAS) influence malignancy and also predict that RAS inhibitors, which are currently used to treat hypertension and cardiovascular disease, might augment cancer therapies. To appreciate this potential hegemony of the RAS in cancer, an expanded comprehension of the cellular actions of this system is needed, as well as a greater focus on translational and in vivo research.
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Affiliation(s)
- Amee J George
- School of Biomedical Sciences, The University of Queensland, St. Lucia, Queensland 4072, Australia
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22
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de Andrade MCC, Affonso R, Fernandes FB, Febba AC, da Silva IDCG, Stella RCR, Marson O, Jubilut GN, Hirata IY, Carmona AK, Corradi H, Acharya KR, Sturrock ED, Casarini DE. Spectroscopic and structural analysis of somatic and N-domain angiotensin I-converting enzyme isoforms from mesangial cells from Wistar and spontaneously hypertensive rats. Int J Biol Macromol 2010; 47:238-43. [PMID: 20435057 DOI: 10.1016/j.ijbiomac.2010.04.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2010] [Revised: 04/23/2010] [Accepted: 04/26/2010] [Indexed: 10/19/2022]
Abstract
Angiotensin I-converting enzyme (ACE) plays a key role in the renin-angiotesin aldosterone cascade. We analysed the secondary structure and structural organization of a purified 65kDa N-domain ACE (nACE) from Wistar rat mesangial cells, a 90 kDa nACE from spontaneously hypertensive rats and a 130 kDa somatic ACE. The C-terminal alignment of the 65 kDa nACE with rat ACE revealed that the former was truncated at Ser(482), and the sequence of the 90 kDa nACE ended at Pro(629). Protein's secondary structure consisted predominantly of alpha-helices. The 90 and 65 kDa isoforms were the most stable in guanidine and at low pH, respectively. Enzymatic activity decreased with loss in secondary structure, except in the case of guanidine HCl where the 90 kDa fragment loses its secondary structure faster than its enzymatic activity. We identified and characterized the activity and stability of these isoforms and these findings would be helpful on the understanding of the role of nACE isoforms in hypertension.
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Affiliation(s)
- Maria C C de Andrade
- Departamento de Medicina, Disciplina de Nefrologia, Universidade Federal de São Paulo, Escola Paulista de Medicina, Botucatu Street 740, Zip Code 04023-900, SP, São Paulo, Brazil
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Sun X, Rentzsch B, Gong M, Eichhorst J, Pankow K, Papsdorf G, Maul B, Bader M, Siems WE. Signal transduction in CHO cells stably transfected with domain-selective forms of murine ACE. Biol Chem 2010; 391:235-244. [DOI: 10.1515/bc.2010.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Abstract
Membrane-bound human angiotensin-converting enzyme (ACE) has been reported to initiate intracellular signaling after interaction with substrates or inhibitors. Somatic ACE is known to contain two distinct, extracellular catalytic centers. We analyzed the signal transduction mechanisms in cells transfected with different forms of murine ACE (mACE) and investigated whether the two domains are similarly involved in these processes. For this purpose, CHO cells were stably transfected with mACE or with its domain-selective mutants. In addition to these modified cellular models, human umbilical vein endothelial cells were used in this study. Signal transduction molecules such as JNK and c-Jun were analyzed after activation of cells with several ACE substrates and inhibitors. ACE-targeting compounds such as substrates, inhibitors, or even the ACE product angiotensin-II induce in mACE-expressing cells a signal transduction response. These processes are also evoked by partially inactivated forms of mACE and finally result in an enhanced cyclooxygenase-2 transcription. Surprisingly, the membrane-bound ACE activity is also influenced by ACE-targeted interventions. Our data suggest that the two catalytic domains of mACE do not function independently but that the signal transduction is influenced by negative cooperativity of the two catalytic domains. This study underlines that ACE indeed has receptor-like properties which occur in a species-specific manner.
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Affiliation(s)
- Xiaoou Sun
- Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, Germany
- Charité, Universitätsmedizin Berlin, D-13353 Berlin, Germany
| | - Brit Rentzsch
- Max-Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany
| | - Maolian Gong
- Max-Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany
| | - Jenny Eichhorst
- Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, Germany
| | - Kristin Pankow
- Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, Germany
- Charité, Universitätsmedizin Berlin, D-13353 Berlin, Germany
| | - Gisela Papsdorf
- Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, Germany
| | - Björn Maul
- Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, Germany
| | - Michael Bader
- Max-Delbrück Center for Molecular Medicine, D-13125 Berlin, Germany
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Lambert DW, Clarke NE, Turner AJ. Not just angiotensinases: new roles for the angiotensin-converting enzymes. Cell Mol Life Sci 2010; 67:89-98. [PMID: 19763395 PMCID: PMC7079792 DOI: 10.1007/s00018-009-0152-x] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2009] [Revised: 08/27/2009] [Accepted: 08/27/2009] [Indexed: 01/07/2023]
Abstract
The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Angiotensin II, the primary bioactive peptide of the RAS, is generated from angiotensin I by angiotensin-converting enzyme (ACE). A homologue of ACE, ACE2, is able to convert angiotensin II to a peptide with opposing effects, angiotensin-(1-7). It is proposed that disturbance of the balance of ACE and ACE2 expression and/or function is important in pathologies in which angiotensin II plays a role. These include cardiovascular and renal disease, lung injury and liver fibrosis. The critical roles of ACE and ACE2 in regulating angiotensin II levels have traditionally focussed attention on their activities as angiotensinases. Recent discoveries, however, have illuminated the roles of these enzymes and of the ACE2 homologue, collectrin, in intracellular trafficking and signalling. This paper reviews the key literature regarding both the catalytic and non-catalytic roles of the angiotensin-converting enzyme gene family.
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Affiliation(s)
- Daniel W Lambert
- Oral and Maxillofacial Pathology, Faculty of Medicine, Dentistry and Health, University of Sheffield, S10 2TA, Sheffield, UK.
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Lucero HA, Kintsurashvili E, Marketou ME, Gavras H. Cell signaling, internalization, and nuclear localization of the angiotensin converting enzyme in smooth muscle and endothelial cells. J Biol Chem 2009; 285:5555-68. [PMID: 20022959 DOI: 10.1074/jbc.m109.074740] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The angiotensin converting enzyme (ACE) catalyzes the extracellular formation of angiotensin II, and degradation of bradykinin, thus regulating blood pressure and renal handling of electrolytes. We have previously shown that exogenously added ACE elicited transcriptional regulation independent of its enzymatic activity. Because transcriptional regulation generates from protein-DNA interactions within the cell nucleus we have investigated the initial cellular response to exogenous ACE and the putative internalization of the enzyme in smooth muscle cells (SMC) and endothelial cells (EC). The following phenomena were observed when ACE was added to cells in culture: 1) it bound to SMC and EC with high affinity (K(d) = 361.5 +/- 60.5 pM) and with a low binding occupancy (B(max) = 335.0 +/- 14.0 molecules/cell); 2) it triggered cellular signaling resulting in late activation of focal adhesion kinase and SHP2; 3) it modulated platelet-derived growth factor receptor-beta signaling; 4) it was endocytosed by SMC and EC; and 5) it transited through the early endosome, partially occupied the late endosome and the lysosome, and was localized to the nuclei. The incorporation of ACE or a fragment of it into the nuclei reached saturation at 120 min, and was preceded by a lag time of 40 min. Internalized ACE was partially cleaved into small fragments. These results revealed that extracellular ACE modulated cell signaling properties, and that SMC and EC have a pathway for delivery of extracellular ACE to the nucleus, most likely involving cell surface receptor(s) and requiring transit through late endosome/lysosome compartments.
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Affiliation(s)
- Héctor A Lucero
- Alapis Research Laboratories, Boston, Massachusetts 02118, USA.
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Gordon K, Balyasnikova IV, Nesterovitch AB, Schwartz DE, Sturrock ED, Danilov SM. Fine epitope mapping of monoclonal antibodies 9B9 and 3G8 to the N domain of angiotensin-converting enzyme (CD143) defines a region involved in regulating angiotensin-converting enzyme dimerization and shedding. ACTA ACUST UNITED AC 2009; 75:136-50. [PMID: 20003136 DOI: 10.1111/j.1399-0039.2009.01416.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A panel of monoclonal antibodies (mAbs) raised against both the N and C domains of angiotensin-I-converting enzyme (ACE, peptidyl dipeptidase, EC 3.4.15.2) have been extensively mapped and have facilitated the study of various aspects of ACE structure and biology. In this study, we characterize two mAbs, 9B9 and 3G8, that recognize the N domain of ACE and that influence shedding and dimerization. Fine epitope mapping was performed, which mapped the epitopes for these mAbs to the N terminal region of the N domain where they overlap to a large extent, despite having different effects on ACE processing. The mAb 3G8 epitope appears to be shielded by the C domain and to be carbohydrate dependent as binding increased significantly as a result of underglycosylation, whereas these factors did not influence mAb 9B9 recognition. Three mutations within the overlapping region of these two epitopes, Q18H, L19E, and Q22A, which decreased mAb 3G8 binding to the soluble N domain, were introduced into full-length somatic ACE (sACE) to determine their influence on ACE expression and processing. Increased ACE expression, cell surface expression, and basal shedding were observed with all three mutations. Furthermore, cross-linking and western blotting of Chinese hamster ovary (CHO) cell lysates detected two distinct ACE dimers, a native and cross-linked dimer. Increasing amounts of the cross-linked dimer were observed for the mutant sACEQ22A, further implicating the overlapping region of the mAb 9B9 and 3G8 epitopes in ACE processing.
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Affiliation(s)
- K Gordon
- Division of Medical Biochemistry, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa
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Kohlstedt K, Gershome C, Trouvain C, Hofmann WK, Fichtlscherer S, Fleming I. Angiotensin-converting enzyme (ACE) inhibitors modulate cellular retinol-binding protein 1 and adiponectin expression in adipocytes via the ACE-dependent signaling cascade. Mol Pharmacol 2009; 75:685-92. [PMID: 19114589 DOI: 10.1124/mol.108.051631] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Inhibitors of the angiotensin-converting enzyme (ACE) decrease angiotensin II production and activate an intracellular signaling cascade that affects gene expression in endothelial cells. Because ACE inhibitors have been reported to delay the onset of type 2 diabetes, we determined ACE signaling-modulated gene expression in endothelial cells and adipocytes. Using differential gene expression analysis, several genes were identified that were 3-fold up- or down-regulated by ramiprilat in cells expressing wild-type ACE versus cells expressing a signaling-dead ACE mutant. One up-regulated gene was the cellular retinol-binding protein 1 (CRBP1). In adipocytes, the overexpression of CRBP1 enhanced (4- to 5-fold) the activity of promoters containing response elements for retinol-dependent nuclear receptors [retinoic acid receptor (RAR) and retinoid X receptor (RXR)] or peroxisome proliferator-activated receptors (PPAR). CRBP1 overexpression also enhanced the promoter activity (by 470 +/- 40%) and expression/release of the anti-inflammatory and antiatherogenic adipokine adiponectin (cellular adiponectin by 196 +/- 24%, soluble adiponectin by 228 +/- 74%). Significantly increased adiponectin secretion was also observed after ACE inhibitor treatment of human preadipocytes, an effect prevented by small interfering RNA against CRBP1. Furthermore, in ob/ob mice, ramipril markedly potentiated both the basal (approximately 2-fold) and rosiglitazonestimulated circulating levels of adiponectin. In patients with coronary artery disease or type 2 diabetes, ACE inhibition also significantly increased plasma adiponectin levels (1.6- or 2.1-fold, respectively). In summary, ACE inhibitors affect adipocyte homeostasis via CRBP1 through the activation of RAR/RXR-PPAR signaling and up-regulation of adiponectin. The latter may contribute to the beneficial effects of ACE inhibitors on the development of type 2 diabetes in patients with an activated renin-angiotensin system.
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Affiliation(s)
- Karin Kohlstedt
- Institute for Vascular Signaling, Johann Wolfgang Goethe University, Frankfurt am Main, Germany.
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Sun X, Wiesner B, Lorenz D, Papsdorf G, Pankow K, Wang P, Dietrich N, Siems WE, Maul B. Interaction of angiotensin-converting enzyme (ACE) with membrane-bound carboxypeptidase M (CPM) - a new function of ACE. Biol Chem 2009; 389:1477-85. [PMID: 18844448 DOI: 10.1515/bc.2008.168] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Angiotensin-converting enzyme (ACE) demonstrates, besides its typical dipeptidyl-carboxypeptidase activity, several unusual functions. Here, we demonstrate with molecular, biochemical, and cellular techniques that the somatic wild-type murine ACE (mACE), stably transfected in Chinese Hamster Ovary (CHO) or Madin-Darby Canine Kidney (MDCK) cells, interacts with endogenous membranal co-localized carboxypeptidase M (CPM). CPM belongs to the group of glycosylphosphatidylinositol (GPI)-anchored proteins. Here we report that ACE, completely independent of its known dipeptidase activities, has GPI-targeted properties. Our results indicate that the spatial proximity between mACE and the endogenous CPM enables an ACE-evoked release of CPM. These results are discussed with respect to the recently proposed GPI-ase activity and function of sperm-bound ACE.
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Affiliation(s)
- Xiaoou Sun
- Leibniz-Institut für Molekulare Pharmakologie, D-13125 Berlin, Germany and Charité-Universitätsmedizin Berlin, D-10117 Berlin, Germany
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Simultaneous determination of ACE activity with 2 substrates provides information on the status of somatic ACE and allows detection of inhibitors in human blood. J Cardiovasc Pharmacol 2008; 52:90-103. [PMID: 18645413 DOI: 10.1097/fjc.0b013e31817fd3bc] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Angiotensin I-converting enzyme (ACE), a key enzyme in cardiovascular pathophysiology, consists of 2 homologous domains, each bearing a Zn-dependent active site. The ratio of the rates of hydrolysis of 2 synthetic substrates, Z-Phe-His-Leu (ZPHL) and Hip-His-Leu (HHL), is characteristic for each type of ACE: somatic 2-domain 1, N-domain 4.5, and C-domain 0.7 (Williams et al, 1996). We hypothesized that inactivation or selective inhibition of the C-domain within the somatic ACE should increase the ratio from 1 toward higher values, whereas inactivation or inhibition of the N-domain should decrease the ratio to lower values. Temperatures in the 40-60 degrees C range cause preferential inactivation of the C-domain in somatic ACE and an increase in the ZPHL/HHL ratio. Determination of the ZPHL/HHL ratio in freshly 100-fold concentrated urine ruled out the existence of the N-domain fragment in human urine, which appears only as a result of long storage. Inhibition of ACE by common inhibitors also increases the ZPHL/HHL ratio for 2-domain ACE, thus providing a sensitive method for the detection of ACE inhibitors in biological fluids. Therefore, simultaneous measurements of ACE activity with 2 substrates (ZPHL and HHL) and calculation of their ratio allow us to monitor the status of the ACE molecule and detect ACE inhibitors (endogenous and exogenous) in human blood and other biological fluids. This method should find wide application in monitoring clinical trials with ACE inhibitors and in the development of the approach for personalized medicine by these effective drugs.
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Shih PA, O’Connor D, Mahata S. Human Genomics in Hypertension. Genomics 2008. [DOI: 10.3109/9781420067064-11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Shih PAB, O'Connor DT. Hereditary determinants of human hypertension: strategies in the setting of genetic complexity. Hypertension 2008; 51:1456-64. [PMID: 18413494 PMCID: PMC2587105 DOI: 10.1161/hypertensionaha.107.090480] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2007] [Accepted: 03/19/2008] [Indexed: 12/28/2022]
Affiliation(s)
- Pei-an Betty Shih
- Department of Medicine, Center for Human Genetics and Genomics, University of California at San Diego, and VA San Diego Healthcare System, La Jolla, CA 92093-0838, USA
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Tschakovsky ME. Introduction to proceedings from the 2005 CSEP symposium “Exercise and the endothelium”. Appl Physiol Nutr Metab 2008; 33:149-50. [DOI: 10.1139/h07-145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
This introduction summarizes the topics addressed in the three companion review papers on various issues surrounding exercise and the endothelium. Leading experts in the field discuss the most recent findings regarding the following: (i) nitric oxide and exercise hyperemia, (ii) the response of the endothelium to exercise training, and (iii) the impact of exercise on the vascular biology of angiotensin as it relates to the vascular endothelium.
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Affiliation(s)
- Michael E. Tschakovsky
- School of Kinesiology and Health Studies, Queen’s University, Kingston, ON K7L 3N6 (e-mail: )
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Bhatnagar V, O'Connor DT, Schork NJ, Salem RM, Nievergelt CM, Rana BK, Smith DW, Bakris GL, Middleton JP, Norris KC, Wright JT, Cheek D, Hiremath L, Contreras G, Appel LJ, Lipkowitz MS. Angiotensin-converting enzyme gene polymorphism predicts the time-course of blood pressure response to angiotensin converting enzyme inhibition in the AASK trial. J Hypertens 2007; 25:2082-92. [PMID: 17885551 PMCID: PMC2792638 DOI: 10.1097/hjh.0b013e3282b9720e] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE It has yet to be determined whether genotyping at the angiotensin-converting enzyme (ACE) locus is predictive of blood pressure response to an ACE inhibitor. METHODS Participants from the African American Study of Kidney Disease and Hypertension trial randomized to the ACE inhibitor ramipril (n = 347) were genotyped at three polymorphisms on ACE, just downstream from the ACE insertion/deletion polymorphism (Ins/Del): G12269A, C17888T, and G20037A. Time to reach target mean arterial pressure ( RESULTS Individuals with a homozygous genotype at G12269A responded significantly faster than those with a heterozygous genotype; the adjusted (average number of medications and baseline mean arterial pressure) hazard ratio (homozygous compared to heterozygous genotype) was 1.86 (95% confidence limits 1.32-3.23; P < 0.001 for G12269A genotype). The adjusted hazard ratio for participants with homozygous ACE haplotypes compared to those heterozygous ACE haplotypes was 1.40 (1.13-1.75; P = 0.003 for haplotype). The ACE genotype effects were specific for ACE inhibition (i.e., not seen among those randomized to a calcium channel blocker), and were independent of population stratification. CONCLUSIONS African-Americans with a homozygous genotype at G12269A or homozygous ACE haplotypes responded to ramipril significantly faster than those with a heterozygous genotype or heterozygous haplotypes, suggesting that heterosis may be an important determinant of responsiveness to an ACE inhibitor. These associations may be a result of biological activity of this polymorphism, or of linkage disequilibrium with nearby variants such as the ACE Ins/Del, perhaps in the regulation of ACE splicing.
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Vankelecom H. Non-hormonal cell types in the pituitary candidating for stem cell. Semin Cell Dev Biol 2007; 18:559-70. [PMID: 17509912 DOI: 10.1016/j.semcdb.2007.04.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2006] [Revised: 02/22/2007] [Accepted: 04/10/2007] [Indexed: 12/17/2022]
Abstract
Hormone balances in the body are primarily governed by the hypothalamus-pituitary system. For its pivotal role, the pituitary gland relies on an assortment of different hormone-producing cell types, the proportions of which dynamically change in response to fluctuating endocrine demands. Mechanisms of pituitary cellular plasticity are at present far from understood, and may include proliferation and transdifferentiation of hormonal cells. Whether new cells also originate by recruitment from stem cells is unsettled, although this idea has frequently been proposed. Here, I will review these data by focusing on the non-hormonal cell types that have been advanced as candidates for the pituitary stem cell position.
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Affiliation(s)
- Hugo Vankelecom
- Laboratory of Cell Pharmacology, Department of Molecular Cell Biology, Campus Gasthuisberg O&N1, Herestraat 49, University of Leuven (K.U.Leuven), B-3000 Leuven, Belgium.
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Abstract
Tissue-specific stem cells are uncovered in a growing number of organs by their molecular expression profile and their potential for self-renewal, multipotent differentiation and tissue regeneration. Whether the pituitary gland also contains a pool of versatile 'master' cells that drive homeostatic, plastic and regenerative cell ontogenesis is at present unknown. Here, I will give an overview of data that may lend support to the existence of stem cells in the postnatal pituitary. During the many decades of pituitary research, various approaches have been used to hunt for the pituitary stem cells. Transplantation and regeneration studies advanced chromophobes as possible source of new hormonal cells. Clonogenicity approaches identified pituitary cells that clonally expand to floating spheres, or to colonies in adherent cell cultures. Behavioural characteristics and changes of marginal, follicular and folliculostellate cells during defined developmental and (patho-)physiological conditions have been interpreted as indicative of a stem cell role. Expression of potential stem cell markers like nestin, as well as topographical localization in the marginal zone around the cleft has also been considered to designate pituitary stem cells. Finally, a 'side population' was recently identified in the postnatal pituitary which in many other tissues represents a stem cell-enriched fraction. Taken together, in the course of the long-standing study of the pituitary, several arguments have been presented to support the existence of stem cells, and multiple cell types have been placed in the spotlight as possible candidates. However, none of these cells has until now unequivocally been shown to meet all quintessential characteristics of stem cells.
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Affiliation(s)
- Hugo Vankelecom
- Laboratory of Cell Pharmacology, Department of Molecular Cell Biology, University of Leuven, Leuven, Belgium.
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Danser AHJ, Batenburg WW, van den Meiracker AH, Danilov SM. ACE phenotyping as a first step toward personalized medicine for ACE inhibitors. Why does ACE genotyping not predict the therapeutic efficacy of ACE inhibition? Pharmacol Ther 2006; 113:607-18. [PMID: 17257685 DOI: 10.1016/j.pharmthera.2006.12.001] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2006] [Revised: 12/06/2006] [Accepted: 12/06/2006] [Indexed: 11/21/2022]
Abstract
Angiotensin (Ang)-converting enzyme (ACE) inhibitors are widely used for the treatment of cardiovascular diseases. Not all patients respond to ACE inhibitors, and it has been suggested that genetic variation might be a useful marker to predict the therapeutic efficacy of these drugs. In particular, the ACE insertion (I)/deletion (D) polymorphism has been investigated in this regard. Despite a decade of intensive research involving the genotyping of thousands of patients, we still do not know whether ACE genotyping helps in predicting the success of ACE inhibition. This review critically addresses the concept that predictive information on therapeutic efficacy of ACE inhibitors might be obtained based on ACE genotyping. It answers the following questions: Do higher ACE levels really result in higher Ang II levels? Is ACE the only converting enzyme in humans? Does ACE inhibition affect ACE expression? Why does ACE have 2 catalytically active domains? What is the relevance of ACE inhibitor-induced signaling through membrane-bound ACE? The review ends with the proposal that ACE phenotyping may prove to be a better first step toward personalized medicine for ACE inhibitors than ACE genotyping.
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Affiliation(s)
- A H Jan Danser
- Department of Pharmacology, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands.
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Abstract
AbstractAngiotensin-converting enzyme (ACE, kininase II) is a plasma membrane zinc metallopeptidase that acts as a key enzyme for the extracellular conversion of vasoactive peptides. Recently, ACE outside-in signalling in endothelial cells has been described. The present study tested the hypothesis that ACE signalling is not restricted to endothelial cells and may act as an additional peptide receptor on human preadipocytes and adipocytes. ACE protein levels were not changed during adipose conversion of human primary preadipocytes. The enzyme was primarily localized to the non-detergent-resistant fraction of the membrane and phosphorylated in non-dividing cells. Antibody arrays of whole cell lysate detected putative ACE-interacting proteins, which all share important roles in cell cycle control and/or apoptosis. These findings suggest that ACE is a versatile molecule, involved both in the regulation of extracellular peptide concentrations and direct intracellular signalling. In human adipose cells ACE may potentially influence exit from the cell cycle, differentiation, and programmed cell death signalling.
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