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Article ; Online: Single-cell profiling identifies ACE

Pham, Trung H M / Xue, Yuan / Brewer, Susan M / Bernstein, Kenneth E / Quake, Stephen R / Monack, Denise M

2023 Volume 9, Issue 1, Page(s) eadd4333

Abstract: Macrophages mediate key antimicrobial responses against intracellular bacterial pathogens, such ... ...

Abstract	Macrophages mediate key antimicrobial responses against intracellular bacterial pathogens, such as
MeSH term(s)	Animals ; Mice ; Salmonella typhimurium/genetics ; Persistent Infection ; Salmonella Infections/genetics ; Macrophages/microbiology ; Granuloma
Language	English
Publishing date	2023-01-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.add4333
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Article ; Online: Diverse biological functions of the renin-angiotensin system.

Rao, Adithi / Bhat, Shabir A / Shibata, Tomohiro / Giani, Jorge F / Rader, Florian / Bernstein, Kenneth E / Khan, Zakir

Medicinal research reviews

2023 Volume 44, Issue 2, Page(s) 587–605

Abstract: The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, ...

Abstract	The renin-angiotensin system (RAS) has been widely known as a circulating endocrine system involved in the control of blood pressure. However, components of RAS have been found to be localized in rather unexpected sites in the body including the kidneys, brain, bone marrow, immune cells, and reproductive system. These discoveries have led to steady, growing evidence of the existence of independent tissue RAS specific to several parts of the body. It is important to understand how RAS regulates these systems for a variety of reasons: It gives a better overall picture of human physiology, helps to understand and mitigate the unintended consequences of RAS-inhibiting or activating drugs, and sets the stage for potential new therapies for a variety of ailments. This review fulfills the need for an updated overview of knowledge about local tissue RAS in several bodily systems, including their components, functions, and medical implications.
MeSH term(s)	Humans ; Renin-Angiotensin System/physiology ; Kidney/metabolism ; Angiotensin II/metabolism ; Peptidyl-Dipeptidase A/metabolism
Chemical Substances	Angiotensin II (11128-99-7) ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2023-11-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	603210-2
ISSN	1098-1128 ; 0198-6325
ISSN (online)	1098-1128
ISSN	0198-6325
DOI	10.1002/med.21996
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Article: The effects of enhancing angiotensin converting enzyme in myelomonocytes on ameliorating Alzheimer's-related disease and preserving cognition.

Danziger, Ron / Fuchs, Dieu-Trang / Koronyo, Yosef / Rentsendorj, Altan / Sheyn, Julia / Hayden, Eric Y / Teplow, David B / Black, Keith L / Fuchs, Sebastien / Bernstein, Kenneth E / Koronyo-Hamaoui, Maya

Frontiers in physiology

2023 Volume 14, Page(s) 1179315

Abstract: This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein ( ... ...

Abstract	This review examines the role of angiotensin-converting enzyme (ACE) in the context of Alzheimer's disease (AD) and its potential therapeutic value. ACE is known to degrade the neurotoxic 42-residue long alloform of amyloid β-protein (Aβ
Language	English
Publishing date	2023-06-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564217-0
ISSN	1664-042X
ISSN	1664-042X
DOI	10.3389/fphys.2023.1179315
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Article ; Online: A Qualitative Study of Systems-Level Factors That Affect Rural Obstetric Nurses' Work During Clinical Emergencies.

Bernstein, Samantha L / Picciolo, Maya / Grills, Elisabeth / Catchpole, Kenneth

Joint Commission journal on quality and patient safety

2023

Abstract: Background: Maternal morbidity and mortality is rising in the United States. Previous studies focus on patient attributes, and most of the national data are based on research performed at urban tertiary care centers. Although it is well understood that ... ...

Abstract	Background: Maternal morbidity and mortality is rising in the United States. Previous studies focus on patient attributes, and most of the national data are based on research performed at urban tertiary care centers. Although it is well understood that nurses affect patient outcomes, there is scant evidence to understand the nurse work system, and no studies have specifically studied rural nurses. The authors sought to understand the systems-level factors affecting rural obstetric nurses when their patients experience clinical deterioration. Methods: The research team used a qualitative descriptive approach, including a modified critical incident technique, in interviews with bedside nurses (n = 7) and physicians (n = 4) to understand what happens when patients experience clinical deterioration. Physicians were included to better understand the systems in which nurses work. Clinicians were interviewed at three rural hospitals in New England, with a mean births per year of 190. Findings: Six systems-level factors/themes were identified: (1) shortages of resources; (2) need for teamwork; (3) physicians' multiple conflicting and simultaneous responsibilities, such as seeing patients in the office while women labor on the hospital floor; (4) need for all team members to be at the top of their game; (5) process issues during high-acuity patient transfer, including difficulty finding available beds at tertiary care centers; and (6) insufficient policies that take low-resource contexts into account, such as requiring two registered nurses to remove emergency medications from the medication cabinet. Conclusion: Rural nurses need policies and protocols that are written with their hospital context in mind. Hospitals may need outside support for content expertise, but policies should be co-created with clinicians with rural practice experience.
Language	English
Publishing date	2023-12-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1189890-2
ISSN	1938-131X ; 1549-425X ; 1553-7250 ; 1070-3241 ; 1549-3741
ISSN (online)	1938-131X ; 1549-425X
ISSN	1553-7250 ; 1070-3241 ; 1549-3741
DOI	10.1016/j.jcjq.2023.12.002
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Article ; Online: Myeloid cell ACE shapes cellular metabolism and function in PCSK-9 induced atherosclerosis.

Cao, DuoYao / Saito, Suguru / Xu, LiMin / Fan, Wei / Li, Xiaomo / Ahmed, Faizan / Jovanovic, Predrag / Shibata, Tomohiro / Che, Mingtian / Bernstein, Ellen A / Gianni, Jorge / Divakaruni, Ajit S / Okwan-Duodu, Derick / Khan, Zakir / Riera, Celine E / Chen, Fanfan / Bernstein, Kenneth E

Frontiers in immunology

2023 Volume 14, Page(s) 1278383

Abstract: The pathogenesis of atherosclerosis is defined by impaired lipid handling by macrophages which increases intracellular lipid accumulation. This dysregulation of macrophages triggers the accumulation of apoptotic cells and chronic inflammation which ... ...

Abstract	The pathogenesis of atherosclerosis is defined by impaired lipid handling by macrophages which increases intracellular lipid accumulation. This dysregulation of macrophages triggers the accumulation of apoptotic cells and chronic inflammation which contributes to disease progression. We previously reported that mice with increased macrophage-specific angiotensin-converting enzyme, termed ACE10/10 mice, resist atherosclerosis in an adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-induced model. This is due to increased lipid metabolism by macrophages which contributes to plaque resolution. However, the importance of ACE in peripheral blood monocytes, which are the primary precursors of lesional-infiltrating macrophages, is still unknown in atherosclerosis. Here, we show that the ACE-mediated metabolic phenotype is already triggered in peripheral blood circulating monocytes and that this functional modification is directly transferred to differentiated macrophages in ACE10/10 mice. We found that Ly-6Clo monocytes were increased in atherosclerotic ACE10/10 mice. The monocytes isolated from atherosclerotic ACE10/10 mice showed enhanced lipid metabolism, elevated mitochondrial activity, and increased adenosine triphosphate (ATP) levels which implies that ACE overexpression is already altered in atherosclerosis. Furthermore, we observed increased oxygen consumption (VO2), respiratory exchange ratio (RER), and spontaneous physical activity in ACE10/10 mice compared to WT mice in atherosclerotic conditions, indicating enhanced systemic energy consumption. Thus, ACE overexpression in myeloid lineage cells modifies the metabolic function of peripheral blood circulating monocytes which differentiate to macrophages and protect against atherosclerotic lesion progression due to better lipid metabolism.
MeSH term(s)	Animals ; Mice ; Atherosclerosis/pathology ; Lipids ; Myeloid Cells/pathology ; Proprotein Convertase 9
Chemical Substances	Lipids ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2023-10-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1278383
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Article ; Online: Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ.

Shibata, Tomohiro / Bhat, Shabir A / Cao, DuoYao / Saito, Suguru / Bernstein, Ellen A / Nishi, Erika / Medenilla, Juliet D / Wang, Erica T / Chan, Jessica L / Pisarska, Margareta D / Tourtellotte, Warren G / Giani, Jorge F / Bernstein, Kenneth E / Khan, Zakir

The Journal of biological chemistry

2023 Volume 300, Issue 1, Page(s) 105486

Abstract: Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, ... ...

Abstract	Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.
MeSH term(s)	Animals ; Female ; Humans ; Male ; Mice ; Adenosine Triphosphate/metabolism ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Fertilization/genetics ; PPAR gamma/genetics ; PPAR gamma/metabolism ; Spermatozoa/drug effects ; Spermatozoa/metabolism ; Testis/enzymology ; Mice, Inbred C57BL ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Mitochondrial Proteins/genetics ; Gene Knockout Techniques ; Oxidative Phosphorylation
Chemical Substances	Adenosine Triphosphate (8L70Q75FXE) ; Angiotensin-Converting Enzyme Inhibitors ; PPAR gamma ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Mitochondrial Proteins
Language	English
Publishing date	2023-11-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.105486
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Article ; Online: Overexpressed angiotensin-converting enzyme in neutrophils suppresses glomerular damage in crescentic glomerulonephritis.

Saito, Suguru / Tatsumoto, Narihito / Cao, Duo-Yao / Nosaka, Nobuyuki / Nishi, Hiroshi / Leal, Daniel N / Bernstein, Ellen / Shimada, Kenichi / Arditi, Moshe / Bernstein, Kenneth E / Yamashita, Michifumi

American journal of physiology. Renal physiology

2022 Volume 323, Issue 4, Page(s) F411–F424

Abstract: While angiotensin-converting enzyme (ACE) regulates blood pressure by producing angiotensin II as part of the renin-angiotensin system, we recently reported that elevated ACE in neutrophils promotes an effective immune response and increases resistance ... ...

Abstract	While angiotensin-converting enzyme (ACE) regulates blood pressure by producing angiotensin II as part of the renin-angiotensin system, we recently reported that elevated ACE in neutrophils promotes an effective immune response and increases resistance to infection. Here, we investigate if such neutrophils protect against renal injury in immune complex (IC)-mediated crescentic glomerulonephritis (GN) through complement. Nephrotoxic serum nephritis (NTN) was induced in wild-type and NeuACE mice that overexpress ACE in neutrophils. Glomerular injury of NTN in NeuACE mice was attenuated with much less proteinuria, milder histological injury, and reduced IC deposits, but presented with more glomerular neutrophils in the early stage of the disease. There were no significant defects in T and B cell functions in NeuACE mice. NeuACE neutrophils exhibited enhanced IC uptake with elevated surface expression of FcγRII/III and complement receptor CR1/2. IC uptake in neutrophils was enhanced by NeuACE serum containing elevated complement C3b. Given no significant complement activation by ACE, this suggests that neutrophil ACE indirectly preactivates C3 and that the C3b-CR1/2 axis and elevated FcγRII/III play a central role in IC elimination by neutrophils, resulting in reduced glomerular injury. The present study identified a novel renoprotective role of ACE in glomerulonephritis; elevated neutrophilic ACE promotes elimination of locally formed ICs in glomeruli via C3b-CR1/2 and FcγRII/III, ameliorating glomerular injury.
MeSH term(s)	Angiotensin II/metabolism ; Animals ; Antigen-Antibody Complex/metabolism ; Complement C3b/metabolism ; Glomerulonephritis/metabolism ; Mice ; Nephritis/metabolism ; Neutrophils/metabolism ; Proteinuria/metabolism
Chemical Substances	Antigen-Antibody Complex ; Angiotensin II (11128-99-7) ; Complement C3b (80295-43-8)
Language	English
Publishing date	2022-08-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	603837-2
ISSN	1522-1466 ; 0363-6127
ISSN (online)	1522-1466
ISSN	0363-6127
DOI	10.1152/ajprenal.00067.2022
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Article ; Online: The non-cardiovascular actions of ACE.

Cao, DuoYao / Veiras, Luciana / Ahmed, Faizan / Shibata, Tomohiro / Bernstein, Ellen A / Okwan-Duodu, Derick / Giani, Jorge F / Khan, Zakir / Bernstein, Kenneth E

Peptides

2022 Volume 152, Page(s) 170769

Abstract: Angiotensin converting enzyme (ACE) is well known for its role producing the vasoconstrictor angiotensin II and ACE inhibitors are commonly used for treating hypertension and cardiovascular disease. However, ACE has many different substrates besides ... ...

Abstract	Angiotensin converting enzyme (ACE) is well known for its role producing the vasoconstrictor angiotensin II and ACE inhibitors are commonly used for treating hypertension and cardiovascular disease. However, ACE has many different substrates besides angiotensin I and plays a role in many different physiologic processes. Here, we discuss the role of ACE in the immune response. Several studies in mice indicate that increased expression of ACE by macrophages or neutrophils enhances the ability of these cells to respond to immune challenges such as infection, neoplasm, Alzheimer's disease, and atherosclerosis. Increased expression of ACE induces increased oxidative metabolism with an increase in cell content of ATP. In contrast, ACE inhibitors have the opposite effect, and in both humans and mice, administration of ACE inhibitors reduces the ability of neutrophils to kill bacteria. Understanding how ACE affects the immune response may provide a means to increase immunity in a variety of chronic conditions now not treated through immune manipulation.
MeSH term(s)	Angiotensin I/metabolism ; Angiotensin-Converting Enzyme Inhibitors/metabolism ; Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Angiotensin-Converting Enzyme Inhibitors/therapeutic use ; Animals ; Hypertension/drug therapy ; Hypertension/metabolism ; Macrophages/metabolism ; Mice ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism
Chemical Substances	Angiotensin-Converting Enzyme Inhibitors ; Angiotensin I (9041-90-1) ; Peptidyl-Dipeptidase A (EC 3.4.15.1)
Language	English
Publishing date	2022-02-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	769028-9
ISSN	1873-5169 ; 0196-9781
ISSN (online)	1873-5169
ISSN	0196-9781
DOI	10.1016/j.peptides.2022.170769
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Article ; Online: The Plethora of Angiotensin-Converting Enzyme-Processed Peptides in Mouse Plasma.

Semis, Margarita / Gugiu, Gabriel B / Bernstein, Ellen A / Bernstein, Kenneth E / Kalkum, Markus

Analytical chemistry

2019 Volume 91, Issue 10, Page(s) 6440–6453

Abstract: Angiotensin-converting enzyme (ACE) converts angiotensin I into the potent vasoconstrictor angiotensin II, which regulates blood pressure. However, ACE activity is also essential for other physiological functions, presumably through processing of ... ...

Abstract	Angiotensin-converting enzyme (ACE) converts angiotensin I into the potent vasoconstrictor angiotensin II, which regulates blood pressure. However, ACE activity is also essential for other physiological functions, presumably through processing of peptides unrelated to angiotensin. The goal of this study was to identify novel natural substrates and products of ACE through a series of mass-spectrometric experiments. This included comparing the ACE-treated and untreated plasma peptidomes of ACE-knockout (KO) mice, validation with select synthetic peptides, and a quantitative in vivo study of ACE substrates in mice with distinct genetic ACE backgrounds. In total, 244 natural peptides were identified ex vivo as possible substrates or products of ACE, demonstrating high promiscuity of the enzyme. ACE prefers to cleave substrates with Phe or Leu at the C-terminal P2' position and Gly in the P6 position. Pro in P1' and Iso in P1 are typical residues in peptides that ACE does not cleave. Several of the novel ACE substrates are known to have biological activities, including a fragment of complement C3, the spasmogenic C3f, which was processed by ACE ex vivo and in vitro. Analyses with N-domain-inactive (NKO) ACE allowed clarification of domain selectivity toward substrates. The in vivo ACE-substrate concentrations in WT, transgenic ACE-KO, NKO, and CKO mice correspond well with the in vitro observations in that higher levels of the ACE substrates were observed when the processing domain was knocked out. This study highlights the vast extent of ACE promiscuity and provides a valuable platform for further investigations of ACE functionality.
MeSH term(s)	Angiotensin-Converting Enzyme Inhibitors/pharmacology ; Animals ; Gene Expression Regulation, Enzymologic/drug effects ; Mice ; Mice, Knockout ; Peptides/metabolism ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; Plasma/enzymology ; Ramipril/pharmacology ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Chemical Substances	Angiotensin-Converting Enzyme Inhibitors ; Peptides ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Ramipril (L35JN3I7SJ)
Language	English
Publishing date	2019-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.8b03828
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Article ; Online: Knockout of ACE-N facilitates improved cardiac function after myocardial infarction.

Suhail, Hamid / Peng, Hongmei / Xu, Jiang / Sabbah, Hani N / Matrougui, Khalid / Liao, Tang-Dong / Ortiz, Pablo A / Bernstein, Kenneth E / Rhaleb, Nour-Eddine

Journal of molecular and cellular cardiology plus

2022 Volume 3

Abstract: Angiotensin-converting enzyme (ACE) ... ...

Abstract	Angiotensin-converting enzyme (ACE) hydrolyzes
Language	English
Publishing date	2022-11-29
Publishing country	Netherlands
Document type	Journal Article
ISSN	2772-9761
ISSN (online)	2772-9761
DOI	10.1016/j.jmccpl.2022.100024
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