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Article: Plasma-reduction for Apheresis Granulocyte transfusions in pediatric patients.

Jung, Yujung / Mallhi, Kanwaldeep K / Alcorn, Kirsten / Saifee, Nabiha H

Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis

2024 Volume 63, Issue 2, Page(s) 103879

Abstract: Granulocyte transfusion (GT) may be used to treat and prevent infections in patients with severe neutropenia or nonfunctioning granulocytes. For pediatric patients, the volume of granulocyte unit transfused is a crucial consideration given smaller blood ... ...

Abstract	Granulocyte transfusion (GT) may be used to treat and prevent infections in patients with severe neutropenia or nonfunctioning granulocytes. For pediatric patients, the volume of granulocyte unit transfused is a crucial consideration given smaller blood volume and increased risk of volume overload compared to adults. There is limited literature on the optimal dosing or the maximum amount of granulocytes that can be tolerated, especially in pediatric patients. Additionally, no consensus exists regarding granulocyte collection method, frequency, or timing of GT initiation. Previous studies have described splitting or limiting collection volume for GT in pediatric patients, but these methods yield lower absolute neutrophil count (ANC) increment. Our blood supplier provides high-volume (0.5-1 L/unit), high-dose apheresis-collected granulocytes from donors stimulated with both granulocyte colony-stimulating factor and steroids. Here, we report cases of two pediatric patients with active infection undergoing bone marrow transplant with dramatic ANC increments (median one-hour ANC increment 5524/µL, interquartile range (IQR) 4417-10087; median 24-hour ANC increment 3880/µL, IQR 2550-5263) after infusing 100 mL plasma-reduced, apheresis collected GT. Our cases indicate that pediatric patients can tolerate 4-6 × 10
MeSH term(s)	Adult ; Humans ; Child ; Granulocytes ; Neutrophils ; Leukocyte Transfusion ; Blood Component Removal ; Blood Donors ; Granulocyte Colony-Stimulating Factor/therapeutic use
Chemical Substances	Granulocyte Colony-Stimulating Factor (143011-72-7)
Language	English
Publishing date	2024-01-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2046795-3
ISSN	1878-1683 ; 1473-0502
ISSN (online)	1878-1683
ISSN	1473-0502
DOI	10.1016/j.transci.2024.103879
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Zs.A 1739: Show issues

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Article: Hematopoietic Stem Cell Therapy for Wiskott-Aldrich Syndrome: Improved Outcome and Quality of Life.

Mallhi, Kanwaldeep K / Petrovic, Aleksandra / Ochs, Hans D

Journal of blood medicine

2021 Volume 12, Page(s) 435–447

Abstract: The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in ... ...

Abstract	The Wiskott-Aldrich syndrome (WAS) is an X-linked disorder caused by mutations in the
Language	English
Publishing date	2021-06-11
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	2587464-0
ISSN	1179-2736
ISSN	1179-2736
DOI	10.2147/JBM.S232650
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Article ; Online: BK Viremia and Changes in Estimated Glomerular Filtration Rate in Children and Young Adults after Hematopoietic Cell Transplantation.

Wychera, Chiara / Imlay, Hannah N / Duke, Elizabeth R / Faino, Anna / Li-Huang, Meei / Stevens-Ayers, Terry / Davis, Chris / Lange-Sperandio, Baerbel / Mallhi, Kanwaldeep K / Hill, Joshua A / Boeckh, Michael / Englund, Janet A / Hingorani, Sangeeta

Transplantation and cellular therapy

2022 Volume 29, Issue 3, Page(s) 187.e1–187.e8

Abstract: Kidney disease in allogeneic hematopoietic cell transplantation (HCT) recipients is associated with increased mortality rates. BK virus (BKV) viremia has been associated with kidney dysfunction in pediatric HCT recipients; however, few studies have ... ...

Abstract	Kidney disease in allogeneic hematopoietic cell transplantation (HCT) recipients is associated with increased mortality rates. BK virus (BKV) viremia has been associated with kidney dysfunction in pediatric HCT recipients; however, few studies have investigated longer-term kidney outcomes in association with BKV in this population. Here we assessed the relationship between BK viremia and changes in estimated glomerular filtration rate (eGFR) in children in the first year post-HCT. We selected 136 patients age ≤26 years who underwent HCT in 2007 to 2018 at a single center and had plasma BK viral load data available at 2 time points, weeks 4 to 7 post-HCT and weeks 10 to 13 post-HCT from prospectively collected stored plasma samples. A total of 272 samples were analyzed for BKV using quantitative PCR. We used multivariate linear models to determine the association of BK viremia and change in eGFR by 1 year post-HCT. Forty percent of the patients (54 of 136) had BKV detection in weeks 4 to 7, 13% of whom (7 of 54) had a BK viral load of ≥10,000 copies/mL, and 46% (62 of 136) had BKV detected in weeks 10 to 13, 34% (21 of 62) of whom had a BK viral load of ≥10,000 copies/mL. The mean decline in eGFR was 25.73 mL/min/1.73 m
MeSH term(s)	Humans ; Child ; Young Adult ; Adult ; Viremia/diagnosis ; Viremia/epidemiology ; Glomerular Filtration Rate ; Kidney ; Kidney Diseases ; Hematopoietic Stem Cell Transplantation ; BK Virus
Language	English
Publishing date	2022-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2022.11.023
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Article ; Online: Risk factors for seasonal human coronavirus lower respiratory tract infection after hematopoietic cell transplantation.

Ogimi, Chikara / Xie, Hu / Waghmare, Alpana / Ueda Oshima, Masumi / Mallhi, Kanwaldeep K / Jerome, Keith R / Leisenring, Wendy M / Englund, Janet A / Boeckh, Michael

Blood advances

2021 Volume 5, Issue 7, Page(s) 1903–1914

Abstract: Data are limited regarding risk factors for lower respiratory tract infection (LRTI) caused by seasonal human coronaviruses (HCoVs) and the significance of virologic documentation by bronchoalveolar lavage (BAL) on outcomes in hematopoietic cell ... ...

Abstract	Data are limited regarding risk factors for lower respiratory tract infection (LRTI) caused by seasonal human coronaviruses (HCoVs) and the significance of virologic documentation by bronchoalveolar lavage (BAL) on outcomes in hematopoietic cell transplant (HCT) recipients. We retrospectively analyzed patients undergoing allogeneic HCT (4/2008-9/2018) with HCoV (OC43/NL63/HKU1/229E) detected by polymerase chain reaction during conditioning or post-HCT. Risk factors for all manifestations of LRTI and progression to LRTI among those presenting with HCoV upper respiratory tract infection (URTI) were analyzed by logistic regression and Cox proportional hazard models, respectively. Mortality rates following HCoV LRTI were compared according to virologic documentation by BAL. A total of 297 patients (61 children and 236 adults) developed HCoV infection as follows: 254 had URTI alone, 18 presented with LRTI, and 25 progressed from URTI to LRTI (median, 16 days; range, 2-62 days). Multivariable logistic regression analyses showed that male sex, higher immunodeficiency scoring index, albumin <3 g/dL, glucose >150 mg/dL, and presence of respiratory copathogens were associated with occurrence of LRTI. Hyperglycemia with steroid use was associated with progression to LRTI (P < .01) in Cox models. LRTI with HCoV detected in BAL was associated with higher mortality than LRTI without documented detection in BAL (P < .01). In conclusion, we identified factors associated with HCoV LRTI, some of which are less commonly appreciated to be risk factors for LRTI with other respiratory viruses in HCT recipients. The association of hyperglycemia with LRTI might provide an intervention opportunity to reduce the risk of LRTI.
MeSH term(s)	Adolescent ; Adult ; Child ; Child, Preschool ; Coronavirus Infections/epidemiology ; Coronavirus Infections/etiology ; Female ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Infant ; Infant, Newborn ; Male ; Middle Aged ; Respiratory Tract Infections/epidemiology ; Respiratory Tract Infections/virology ; Retrospective Studies ; Risk Factors ; Seasons ; United States ; Young Adult
Language	English
Publishing date	2021-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2020003865
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Article ; Online: Hematopoietic Cell Transplantation for Congenital Dyserythropoietic Anemia: A Report from the Pediatric Transplant and Cellular Therapy Consortium.

Transplantation and cellular therapy

2022 Volume 28, Issue 6, Page(s) 329.e1–329.e9

Abstract: Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective ... ...

Abstract	Hematopoietic cell transplantation (HCT) is the sole curative option for congenital dyserythropoietic anemia (CDA), a rare type of hemolytic anemia characterized by anemia, ineffective erythropoiesis, and secondary hemochromatosis. In this retrospective multicenter study, we report the outcomes of children with CDA who underwent HCT at participating Pediatric Transplantation and Cellular Therapy Consortium centers. Clinical information on HCT and associated outcomes was collected retrospectively using a common questionnaire. Data were analyzed using descriptive statistics and appropriate analysis. Eighteen patients with CDA who underwent allogeneic HCT between 2002 and 2020 were identified. The majority of patients (n = 13) had CDA type II, and the remainder had either CDA type I (n = 2) or CDA of unknown type (n = 3). Mutations were identified in 7 patients (39%), including SEC23B in 5, GATA1 in 1, and abnormality of chromosome 20 in 1. Thirteen patients had evidence of iron overload pre-HCT and received chelation therapy for a median duration of 10 months (range, 2 months to 17 years) pre-HCT. The median age at the time of HCT was 5.5 years (range, 0.7 to 26 years). Donors were HLA-matched (sibling, 4; unrelated, 10) and mismatched (haploidentical, 1; unrelated, 3). Graft sources were bone marrow in 15 patients, umbilical cord blood in 2 patients, or both in 1 patient. Conditioning included busulfan-based myeloablative (67%), fludarabine-based reduced-intensity (27%), or nonmyeloablative (6%) regimens. Five patients developed veno-occlusive disease, and 4 had viral reactivation. The cumulative incidence of acute graft-versus-host disease (GVHD) was 33%, and that of chronic GVHD was 22%. Four patients (22%) experienced graft failure; all engrafted following either a second HCT (n = 2) or third HCT (n = 2) but sustained considerable morbidities (3 GVHD, 1 death, 2 viral reactivation). With a median follow-up of 3.2 years (range, 0.6 to 14 years)), the 2-year overall survival, event-free survival (EFS), and GVHD-free EFS were 88% (95% confidence interval [CI], 73% to 100%), 65% (95% CI, 45% to 92%), and 60% (95% CI, 40% to 88%), respectively. Univariate analysis did not identify any patient- or transplantation-related variables impacting outcomes. Our study indicates that HCT can be curative for patients with CDA. Strategies such as aggressive chelation, use of preconditioning therapy, and early HCT in the presence of a suitable donor before comorbidities occur are needed to improve engraftment without increasing the risk for toxicity and mortality.
MeSH term(s)	Anemia, Dyserythropoietic, Congenital/genetics ; Child ; Graft vs Host Disease/etiology ; Hematopoietic Stem Cell Transplantation/adverse effects ; Humans ; Retrospective Studies ; Transplantation Conditioning/adverse effects
Language	English
Publishing date	2022-03-11
Publishing country	United States
Document type	Journal Article ; Multicenter Study
ZDB-ID	3062231-1
ISSN	2666-6367
ISSN (online)	2666-6367
DOI	10.1016/j.jtct.2022.03.007
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Article ; Online: HLA-Haploidentical Hematopoietic Cell Transplantation for Treatment of Nonmalignant Diseases Using Nonmyeloablative Conditioning and Post-Transplant Cyclophosphamide.

Mallhi, Kanwaldeep K / Srikanthan, Meera A / Baker, Kelsey K / Frangoul, Haydar A / Torgerson, Troy R / Petrovic, Aleksandra / Geddis, Amy E / Carpenter, Paul A / Baker, K Scott / Sandmaier, Brenda M / Thakar, Monica S / Skoda-Smith, Suzanne / Kiem, Hans-Peter / Storb, Rainer / Woolfrey, Ann E / Burroughs, Lauri M

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

2020 Volume 26, Issue 7, Page(s) 1332–1341

Abstract: Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT ... ...

Abstract	Allogeneic hematopoietic cell transplant (HCT) is often the only curative therapy for patients with nonmalignant diseases; however, many patients do not have an HLA-matched donor. Historically, poor survival has been seen after HLA-haploidentical HCT because of poor immune reconstitution, increased infections, graft-versus-host disease (GVHD), and graft failure. Encouraging results have been reported using a nonmyeloablative T cell-replete HLA-haploidentical transplant approach in patients with hematologic malignancies. Here we report the outcomes of 23 patients with various nonmalignant diseases using a similar approach. Patients received HLA-haploidentical bone marrow (n = 17) or granulocyte colony-stimulating factor-mobilized peripheral blood stem cell (n = 6) grafts after conditioning with cyclophosphamide 50 mg/kg, fludarabine 150 mg/m
MeSH term(s)	Cyclophosphamide/therapeutic use ; Graft vs Host Disease/therapy ; HLA Antigens ; Haplotypes ; Hematologic Neoplasms/therapy ; Hematopoietic Stem Cell Transplantation ; Humans ; Transplantation Conditioning ; Transplantation, Homologous
Chemical Substances	HLA Antigens ; Cyclophosphamide (8N3DW7272P)
Language	English
Publishing date	2020-03-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1474865-4
ISSN	1523-6536 ; 1083-8791
ISSN (online)	1523-6536
ISSN	1083-8791
DOI	10.1016/j.bbmt.2020.03.018
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Article ; Online: Allele-Level HLA Matching Impacts Key Outcomes Following Umbilical Cord Blood Transplantation for Inherited Metabolic Disorders.

Mallhi, Kanwaldeep K / Smith, Angela R / DeFor, Todd E / Lund, Troy C / Orchard, Paul J / Miller, Weston P

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

2016 Volume 23, Issue 1, Page(s) 119–125

Abstract: Allogeneic hematopoietic stem cell transplantation has demonstrated efficacy for numerous inherited metabolic disorders (IMDs). Umbilical cord blood transplant (UCBT) is increasingly used as a graft source in IMDs, but little is known of the impact of ... ...

Abstract	Allogeneic hematopoietic stem cell transplantation has demonstrated efficacy for numerous inherited metabolic disorders (IMDs). Umbilical cord blood transplant (UCBT) is increasingly used as a graft source in IMDs, but little is known of the impact of cord blood unit (CBU)/recipient HLA allelic disparity on key outcomes following UCBT for IMD. We reviewed outcomes of 106 consecutive first, single UCBTs for IMD at the University of Minnesota with regard to CBU/recipient HLA allelic matching (HLA-A, -B, -C, and -DRB1). The median age at UCBT was 1 year, and 87 patients (82%) received myeloablative conditioning. Primary diagnoses were Hurler syndrome (41%), cerebral adrenoleukodystrophy (35%), metachromatic leukodystrophy/globoid cell leukodystrophy (9%), and other (16%). The 5-year overall survival (OS) for the entire cohort was 70% (95% confidence interval, 59% to 79%). Rates of severe acute and chronic graft-versus-host disease were low (6% for each). CBU/recipient HLA conventional matching was based on antigen-level matching at HLA-A and -B, and on allele-level matching at HLA-DRB1. Of 46 conventional matched UCBTs, 20 (43%) were mismatched at 1 or more alleles. Of 49 conventional 5/6 UCBTs, 30 (61%) were mismatched at ≥2 alleles and 19 (39%) were mismatched at ≥3 alleles. Within the 6/6 conventional match stratum, comparisons of key outcomes between allele-matched and allele-mismatched UCBT were as follows: 5-year OS, 88% versus 42% (P < .01); 1-year engrafted survival (ES) with ≥90% donor chimerism, 73% versus 60% (P = .33); graft failure, 8% versus 30% (P = .05); and transplantation-related mortality (TRM), 8% versus 30% (P = .04). For patients undergoing conventional 5/6 HLA-matched UCBT, better allelic matching was associated with similar outcomes: 5-year OS, 77% versus 74% (P = .72); 1-year ES, 73% versus 47% (P = .06); graft failure, 17% versus 42% (P = .05); and TRM, 10% versus 16% (P = .54). On multivariable analyses, fewer allele-level mismatches within each conventional match stratum continued to predict more favorable outcomes following UCBT. These data provide evidence that allele-level HLA matching considerations within a conventional HLA match stratum may better predict outcomes of interest after UCBT for IMD. Larger studies are warranted to confirm these findings and explore other allele-level HLA match dynamics.
MeSH term(s)	Adolescent ; Adrenoleukodystrophy/mortality ; Adrenoleukodystrophy/therapy ; Adult ; Alleles ; Child ; Child, Preschool ; Chimerism ; Cord Blood Stem Cell Transplantation/methods ; Cord Blood Stem Cell Transplantation/mortality ; Cord Blood Stem Cell Transplantation/standards ; Graft Survival ; Graft vs Host Disease/etiology ; HLA Antigens/analysis ; HLA-DRB1 Chains/genetics ; Histocompatibility ; Humans ; Infant ; Metabolism, Inborn Errors/mortality ; Metabolism, Inborn Errors/therapy ; Mucopolysaccharidosis I/mortality ; Mucopolysaccharidosis I/therapy ; Survival Analysis ; Treatment Outcome ; Young Adult
Chemical Substances	HLA Antigens ; HLA-DRB1 Chains
Language	English
Publishing date	2016-10-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	1474865-4
ISSN	1523-6536 ; 1083-8791
ISSN (online)	1523-6536
ISSN	1083-8791
DOI	10.1016/j.bbmt.2016.10.019
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Article: A novel plasma membrane Ca(2+)-pump inhibitor: caloxin 1A1.

Pande, Jyoti / Mallhi, Kanwaldeep K / Grover, Ashok K

European journal of pharmacology

2005 Volume 508, Issue 1-3, Page(s) 1–6

Abstract: The plasma membrane Ca(2+)-Mg(2+)-ATPase is a Ca(2+)-pump that expels Ca2+ from cells. Here we report caloxin 1A1-a novel peptide inhibitor (Ki=100 microM) of plasma membrane Ca(2+)-pump-obtained by screening a cysteine bridge-constrained random peptide ... ...

Abstract	The plasma membrane Ca(2+)-Mg(2+)-ATPase is a Ca(2+)-pump that expels Ca2+ from cells. Here we report caloxin 1A1-a novel peptide inhibitor (Ki=100 microM) of plasma membrane Ca(2+)-pump-obtained by screening a cysteine bridge-constrained random peptide library for binding to the first extracellular domain of plasma membrane Ca(2+)-pump. Dithiothreitol removed the inhibition indicating that the constraint imposed by the cysteine bridge is required for the inhibition. Caloxin 1A1 also inhibited the fast twitch sarcoplasmic reticulum Ca(2+)-Mg(2+)-ATPase although weakly. Glutathione dimers (containing a cysteine bridge) inhibited the Ca(2+)-Mg(2+)-ATPase activity of sarcoplasmic reticulum Ca(2+)-Mg(2+)-ATPase, but not that of plasma membrane Ca(2+)-pump. Caloxin 1A1 stabilised Ca(2+)-dependent formation of the acid stable 140-kDa acylphosphate which is a partial reaction of this enzyme. Thus caloxin 1A1 inhibits the plasma membrane Ca(2+)-pump by perturbing the first extracellular domain indicating that the transmembrane domains 1 and 2 play a role in its reaction cycle. This finding is consistent with rearrangements that occur in transmembrane helices 1 and 2 during reaction cycle of sarcoplasmic reticulum Ca(2+)-pump. Caloxin 1A1 caused an increase in cytosolic Ca2+ concentration in endothelial cells.
MeSH term(s)	Amino Acid Sequence ; Animals ; Ca(2+) Mg(2+)-ATPase/antagonists & inhibitors ; Ca(2+) Mg(2+)-ATPase/metabolism ; Calcium/metabolism ; Cell Membrane/enzymology ; Cells, Cultured ; Coronary Vessels/cytology ; Coronary Vessels/drug effects ; Coronary Vessels/metabolism ; Dithiothreitol/pharmacology ; Dose-Response Relationship, Drug ; Endothelial Cells/drug effects ; Endothelial Cells/metabolism ; Erythrocyte Membrane/drug effects ; Erythrocyte Membrane/enzymology ; Glutathione/pharmacology ; Humans ; Kinetics ; Membrane Proteins/chemistry ; Membrane Proteins/genetics ; Membrane Proteins/pharmacology ; Molecular Sequence Data ; Peptide Library ; Peptides/chemistry ; Peptides/genetics ; Peptides/pharmacology ; Phosphates/metabolism ; Sarcoplasmic Reticulum/drug effects ; Sarcoplasmic Reticulum/enzymology ; Swine
Chemical Substances	Membrane Proteins ; Peptide Library ; Peptides ; Phosphates ; caloxin 1A1 ; Ca(2+) Mg(2+)-ATPase (EC 3.6.1.-) ; Glutathione (GAN16C9B8O) ; Calcium (SY7Q814VUP) ; Dithiothreitol (T8ID5YZU6Y)
Language	English
Publishing date	2005-01-31
Publishing country	Netherlands
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80121-5
ISSN	1879-0712 ; 0014-2999
ISSN (online)	1879-0712
ISSN	0014-2999
DOI	10.1016/j.ejphar.2004.11.057
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Article: Role of third extracellular domain of plasma membrane Ca2+-Mg2+-ATPase based on the novel inhibitor caloxin 3A1.

Pande, Jyoti / Mallhi, Kanwaldeep K / Grover, Ashok K

Cell calcium

2005 Volume 37, Issue 3, Page(s) 245–250

Abstract: The plasma membrane Ca2+ pump (PMCA) is a Ca2+-Mg2+-ATPase that expels Ca2+ from cells to help them maintain low concentrations of cytosolic Ca2+ ([Ca2+]i). It contains five putative extracellular domains (PEDs). Earlier we had reported that binding to ... ...

Abstract	The plasma membrane Ca2+ pump (PMCA) is a Ca2+-Mg2+-ATPase that expels Ca2+ from cells to help them maintain low concentrations of cytosolic Ca2+ ([Ca2+]i). It contains five putative extracellular domains (PEDs). Earlier we had reported that binding to PED2 leads to PMCA inhibition. Mutagenesis of residues in transmembrane domain 6 leads to loss of PMCA activity. PED3 connects transmembrane domains 5 and 6. PED3 is only five amino acid residues long. By screening a phage display library, we obtained a peptide sequence that binds this target. After examining a number of peptides related to this original sequence, we selected one that inhibits the PMCA pump (caloxin 3A1). Caloxin 3A1 inhibits PMCA but not the sarcoplasmic reticulum Ca2+-pump. Caloxin 3A1 did not inhibit formation of the 140 kDa acylphosphate intermediate from ATP or its degradation. Thus, PEDs play a role in the reaction cycle of PMCA even though sites for binding to the substrates Ca2+ and Mg-ATP2-, and the activator calmodulin are all in the cytosolic domains of PMCA. In endothelial cells exposed to low concentration of a Ca2+-ionophore, caloxin 3A1 caused a further increase in [Ca2+]i proving its ability to inhibit PMCA pump extracellularly. Thus, even though PED3 is the shortest PED, it plays key role in the PMCA function.
MeSH term(s)	Animals ; Ca(2+) Mg(2+)-ATPase/antagonists & inhibitors ; Ca(2+) Mg(2+)-ATPase/physiology ; Calcium/metabolism ; Cell Membrane/enzymology ; Coronary Vessels/cytology ; Endothelium, Vascular/cytology ; Erythrocyte Membrane/enzymology ; Humans ; Oligopeptides/pharmacology ; Peptides/pharmacology ; Protein Structure, Tertiary/physiology ; Sus scrofa
Chemical Substances	Oligopeptides ; Peptides ; caloxin 3A1 ; Ca(2+) Mg(2+)-ATPase (EC 3.6.1.-) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2005-03
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	757687-0
ISSN	1532-1991 ; 0143-4160
ISSN (online)	1532-1991
ISSN	0143-4160
DOI	10.1016/j.ceca.2004.10.004
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Article: Aortic smooth muscle and endothelial plasma membrane Ca2+ pump isoforms are inhibited differently by the extracellular inhibitor caloxin 1b1.

Pande, Jyoti / Mallhi, Kanwaldeep K / Sawh, Ahilya / Szewczyk, Magdalena M / Simpson, Fiona / Grover, Ashok K

American journal of physiology. Cell physiology

2006 Volume 290, Issue 5, Page(s) C1341–9

Abstract: Plasma membrane Ca(2+) pumps (PMCA) that expel Ca(2+) from cells are encoded by four genes (PMCA1-4). In this study, we show that aortic endothelium and smooth muscle differ in their PMCA isoform mRNA expression: endothelium expressed predominantly PMCA1, ...

Abstract	Plasma membrane Ca(2+) pumps (PMCA) that expel Ca(2+) from cells are encoded by four genes (PMCA1-4). In this study, we show that aortic endothelium and smooth muscle differ in their PMCA isoform mRNA expression: endothelium expressed predominantly PMCA1, and smooth muscle expressed PMCA4 and a lower level of PMCA1. In this study, we report a novel peptide (caloxin 1b1, obtained by screening for binding to extracellular domain 1 of PMCA4), which inhibited PMCA extracellularly, selectively, and had a higher affinity for PMCA4 than PMCA1. It inhibited the PMCA Ca(2+)-Mg(2+)-ATPase activity in leaky erythrocyte ghosts (mainly PMCA4) with a K(i) value of 46 +/- 5 microM, making it 10x more potent than the previously reported caloxin 2a1. It was isoform selective because it inhibited the PMCA1 Ca(2+)-Mg(2+)-ATPase in human embryonic kidney-293 cells with a higher K(i) value (105 +/- 11 microM) than for PMCA4. Caloxin 1b1 was selective in that it did not inhibit other ATPases. Because caloxin 1b1 had been selected to bind to an extracellular domain of PMCA, it could be added directly to cells and tissues to examine its effects on smooth muscle and endothelium. In de-endothelialized aortic rings, caloxin 1b1 (200 microM) produced a contraction. It also increased the force of contraction produced by a submaximum concentration of phenylephrine. In aortic rings with endothelium intact, precontracted with phenylephrine and relaxed partially with a submaximum concentration of carbachol, caloxin 1b1 increased the force of contraction rather than potentiating the endothelium-dependent relaxation. In cultured cells, caloxin 1b1 increased the cytosolic [Ca(2+)] more in arterial smooth muscle cells than in endothelial cells. Thus caloxin 1b1 is the first highly selective extracellular PMCA inhibitor that works better on vascular smooth muscle than on endothelium.
MeSH term(s)	Animals ; Aorta/drug effects ; Aorta/physiology ; Calcium-Transporting ATPases/chemistry ; Calcium-Transporting ATPases/metabolism ; Cell Membrane/drug effects ; Cell Membrane/physiology ; Dose-Response Relationship, Drug ; Endothelium, Vascular/drug effects ; Endothelium, Vascular/physiology ; Humans ; Male ; Muscle Contraction/drug effects ; Muscle Contraction/physiology ; Muscle, Smooth, Vascular/drug effects ; Muscle, Smooth, Vascular/physiology ; Peptides/administration & dosage ; Protein Isoforms/chemistry ; Protein Isoforms/metabolism ; Rats ; Rats, Inbred WKY ; Structure-Activity Relationship
Chemical Substances	Peptides ; Protein Isoforms ; caloxin 1b1 ; Calcium-Transporting ATPases (EC 7.2.2.10)
Language	English
Publishing date	2006-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	392098-7
ISSN	1522-1563 ; 0363-6143
ISSN (online)	1522-1563
ISSN	0363-6143
DOI	10.1152/ajpcell.00573.2005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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