Male-specific cardiac pathologies in mice lacking either the A or B subunit of factor XIII

2008 ◽  
Vol 99 (02) ◽  
pp. 401-408 ◽  
Author(s):  
Masayoshi Souri ◽  
Shiori Koseki-Kuno ◽  
Naoki Takeda ◽  
Mitsunori Yamakawa ◽  
Yasuchika Takeishi ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Cardiac Fibrosis ◽  
Survival Rates ◽  
Heart Tissue ◽  
Wild Type ◽  
B Subunit ◽  
Reparative Process ◽  
Male Specific ◽  
Fxiii Deficiency

SummaryFactor XIII (FXIII) is a proenzyme of plasma transglutaminase consisting of enzymatic A subunits (FXIII-A) and non-catalytic B subunits (FXIII-B), and acts in haemostasis and wound healing. We generated mice lacking either FXIII-A or FXIII-B to investigate the physiological functions of FXIII in vivo. A longitudinal study was carried out using the gene-targeted mice to explore the possible effects of FXIII deficiency on aging. Survival rates of FXIII-A-/- males decreased to approximately 50% at 10 months after birth, although most FXIII-A-/- females and both genders of wild-type mice survived. Four FXIII-A-/- males died of severe intra-thoracic haemorrhage, and a large haematoma was found in their hearts. Haemorrhage, haemosiderin deposition and/or fibrosis were observed in the hearts of other dead FXIII-A-/- males. Fibrosis together with haemosiderin deposition was also found in the hearts of FXIII-A-/- males sacrificed. The in-vivo cardiac function was normal in FXIII-A-/- mice when compared with wild-type mice despite the presence of significant cardiac fibrosis. Although survival rates for both genders of the FXIII-B-/- and wild-type mice did not differ, mild fibrosis together with haemosiderin deposits were only found in the hearts of the sacrificed FXIII-B-/- males. Carditis and fibrosis in FXIII-deficient mice might be caused by a faulty or delayed reparative process that was initiated by abnormal haemorrhagic events within heart tissue. It is important therefore to examine possible cardiac involvement in human patients with congenital FXIII deficiency.

Impaired clot retraction in factor XIII A subunit–deficient mice

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1277-1279 ◽  
Author(s):  
Kohji Kasahara ◽  
Masayoshi Souri ◽  
Mizuho Kaneda ◽  
Toshiaki Miki ◽  
Naomasa Yamamoto ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Factor Xiii ◽  
Platelet Rich Plasma ◽  
Tissue Transglutaminase ◽  
Adenosine Diphosphate ◽  
Wild Type ◽  
Clot Retraction ◽  
A Subunit ◽  
Fxiii Deficiency

Abstract Factor XIII (FXIII) is a plasma transglutaminase that cross-links fibrin monomers, α2-plasmin inhibitor, and so forth. Congenital FXIII deficiency causes lifelong bleeding symptoms. To understand the molecular pathology of FXIII deficiency in vivo, its knockout mice have been functionally analyzed. Because prolonged bleeding times, a sign of defective/abnormal primary hemostasis, were commonly observed in 2 separate lines of FXIII A subunit (FXIII-A) knockout mice, a possible role or roles of FXIII in platelet-related function was investigated in the present study. Although platelet aggregation induced by adenosine diphosphate or collagen was normal, clot retraction (CR) was lost in the platelet-rich plasma (PRP) of FXIII-A knockout mice. In contrast, there was no CR impairment in the PRP of tissue transglutaminase-knockout mice compared with that of wild-type mice. Furthermore, a transglutaminase inhibitor, cystamine, halted CR in the PRP of wild-type mice. These results indicate that the enzymatic activity of FXIII is necessary for CR, at least in mice.

Abstract 229: TNF Receptor 1 Signaling Is Critically Involved in Mediating Angiotensin II-Induced Cardiac Fibrosis and Dysfunction

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Sandra B Haudek ◽  
Jeff Crawford ◽  
Erin Reineke ◽  
Alberto A Allegre ◽  
George E Taffet ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Fibrosis ◽  
Smooth Muscle Actin ◽  
Protein A ◽  
Ang Ii ◽  
Wild Type ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reactive Fibrosis

Angiotensin-II (Ang-II) plays a key role in the development of cardiomyopathies, as it is associated with many conditions involving heart failure and pathologic hypertrophy. Using a murine model of Ang-II infusion, we found that Ang-II induced the synthesis of monocyte chemoattractant protein 1 (MCP-1) that mediated the uptake of CD34 + /CD45 + monocytic cells into the heart. These precursor cells differentiated into collagen-producing fibroblasts and were responsible for the Ang-II-induced development of reactive fibrosis. Preliminary in vitro data using our monocyte-to-fibroblast differentiation model, suggested that Ang-II required the presence of TNF to induce fibroblast maturation from monocytes. In vivo, they indicated that in mice deficient of both TNF receptors (TNFR1 and TNFR2), Ang-II-induced fibrosis was absent. We now assessed the hypothesis that specific TNFR1 signaling is necessary for Ang-II-mediated cardiac fibrosis. Mice deficient in either TNFR1 (TNFR1-KO) or TNFR2 (TNFR2-KO) were subjected to continuous infusion of Ang-II for 1 to 6 weeks (n=6-8/group). Compared to wild-type, we found that in TNFR1-KO, but not in TNFR2-KO mouse hearts, collagen deposition was attenuated, as was cardiac α-smooth muscle actin protein (a marker for activated fibroblasts). When we isolated viable cardiac fibroblasts and characterized them by flow cytometry, we found that Ang-II infusion in TNFR1-KO, but not in TNFR2-KO, resulted in a marked decrease of CD34 + /CD45 + cells. Quantitative RT-PCR demonstrated a striking reduction of type 1 and 3 collagen, as well of MCP-1 mRNA expression in TNFR1-KO mouse hearts. Further measurements of cardiovascular parameters indicated that TNFR1-KO animals developed lesser Ang-II-mediated LV remodeling, smaller changes in E-linear deceleration times/rates over time, and displayed a lower Tei index (a heart rate independent marker of cardiac function), indicating less stiffness in TNFR1-KO hearts compared to wild-type and TNFR2-KO hearts. The data suggest that Ang-II-dependent cardiac fibrosis requires TNF and its signaling through TNFR1 which enhances the induction of MCP-1 and uptake of monocytic fibroblast precursors that are associated with reactive fibrosis and cardiac remodeling and function.

Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2667-2672 ◽  
Author(s):  
Shiori Koseki ◽  
Masayoshi Souri ◽  
Shinichiro Koga ◽  
Mitsunori Yamakawa ◽  
Tsutomu Shichishima ◽  
...  
Keyword(s):  
Factor Xiii ◽  
Novel Mutation ◽  
Japanese Patients ◽  
Type I ◽  
B Subunit ◽  
Expression Studies ◽  
I Factor ◽  
Electron Microscopes ◽  
Cellular Pathology

Abstract Two Japanese patients were newly diagnosed as having B subunit (XIIIB) deficiency of factor XIII (former type I deficiency). Both patients have a previously described one-base deletion at the boundary between intron A/exon II in the XIIIB gene, heterozygously or homozygously. A founder effect was proposed for this mutation because 3 unrelated patients with XIIIB deficiency also share 2 3′-polymorphisms. In one patient heterozygous for the above mutation, a novel mutation was also identified: a deletion of guanosine in exon IX (delG) of the XIIIB gene. To understand the molecular and cellular pathology of the delG mutation, expression studies were performed using a cultured mammalian cell line. Pulse-chase experiments showed that a resultant truncated XIIIB remained inside the cells and could not be secreted into the culture medium. Furthermore, immunocytochemical examinations by epifluorescence, confocal, and electron microscopes indicated impaired intracellular transportation of the truncated XIIIB from the endoplasmic reticulum to the Golgi apparatus. No mutations in the gene for the A subunit (XIIIA) were identified in this patient. Therefore, secretion of the truncated XIIIB must also be impaired in vivo, leading to a secondary XIIIA deficiency. These results support a previous conclusion that genetic defects of XIIIB are the basis for the former type I factor XIII deficiency.

scholarly journals Rubredoxin:Oxygen Oxidoreductase Enhances Survival of Desulfovibrio vulgaris Hildenborough under Microaerophilic Conditions

2006 ◽  
Vol 188 (17) ◽  
pp. 6253-6260 ◽  
Author(s):  
Janine D. Wildschut ◽  
R. Michael Lang ◽  
Johanna K. Voordouw ◽  
Gerrit Voordouw
Keyword(s):  
Single Cells ◽  
Survival Rates ◽  
Superoxide Reductase ◽  
Desulfovibrio Vulgaris ◽  
Wild Type ◽  
Close Proximity ◽  
Ros Formation ◽  
Similar Survival ◽  
Microaerophilic Conditions

ABSTRACT Genes for superoxide reductase (Sor), rubredoxin (Rub), and rubredoxin:oxygen oxidoreductase (Roo) are located in close proximity in the chromosome of Desulfovibrio vulgaris Hildenborough. Protein blots confirmed the absence of Roo from roo mutant and sor-rub-roo (srr) mutant cells and its presence in sor mutant and wild-type cells grown under anaerobic conditions. Oxygen reduction rates of the roo and srr mutants were 20 to 40% lower than those of the wild type and the sor mutant, indicating that Roo functions as an O2 reductase in vivo. Survival of single cells incubated for 5 days on agar plates under microaerophilic conditions (1% air) was 85% for the sor, 4% for the roo, and 0.7% for the srr mutant relative to that of the wild type (100%). The similar survival rates of sor mutant and wild-type cells suggest that O2 reduction by Roo prevents the formation of reactive oxygen species (ROS) under these conditions; i.e., the ROS-reducing enzyme Sor is only needed for survival when Roo is missing. In contrast, the sor mutant was inactivated much more rapidly than the roo mutant when liquid cultures were incubated in 100% air, indicating that O2 reduction by Roo and other terminal oxidases did not prevent ROS formation under these conditions. Competition of Sor and Roo for limited reduced Rub was suggested by the observation that the roo mutant survived better than the wild type under fully aerobic conditions. The roo mutant was more strongly inhibited than the wild type by the nitric oxide (NO)-generating compound S-nitrosoglutathione, indicating that Roo may also serve as an NO reductase in vivo.

scholarly journals Cardiac-Specific PID1 Overexpression Enhances Pressure Overload-Induced Cardiac Hypertrophy in Mice

2015 ◽  
Vol 35 (5) ◽  
pp. 1975-1985 ◽  
Author(s):  
Yaoqiu Liu ◽  
Yahui Shen ◽  
Jingai Zhu ◽  
Ming Liu ◽  
Xing Li ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Mapk Pathway ◽  
Pressure Overload ◽  
Wild Type Mouse ◽  
Heart Tissue ◽  
Wild Type ◽  
Heart Transplants ◽  
Over Expression

Background/Aims: PID1 was originally described as an insulin sensitivity relevance protein, which is also highly expressed in heart tissue. However, its function in the heart is still to be elucidated. Thus this study aimed to investigate the role of PID1 in the heart in response to hypertrophic stimuli. Methods: Samples of human failing hearts from the left ventricles of dilated cardiomyopathy (DCM) patients undergoing heart transplants were collected. Transgenic mice with cardiomyocyte-specific overexpression of PID1 were generated, and cardiac hypertrophy was induced by transverse aortic constriction (TAC). The extent of cardiac hypertrophy was evaluated by echocardiography as well as pathological and molecular analyses of heart samples. Results: A significant increase in PID1 expression was observed in failing human hearts and TAC-treated wild-type mouse hearts. When compared with TAC-treated wild-type mouse hearts, PID1-TG mouse showed a significant exacerbation of cardiac hypertrophy, fibrosis, and dysfunction. Further analysis of the signaling pathway in vivo suggested that these adverse effects of PID1 were associated with the inhibition of AKT, and activation of MAPK pathway. Conclusion: Under pathological conditions, over-expression of PID1 promotes cardiac hypertrophy by regulating the Akt and MAPK pathway.

miR-19a/19b-loaded exosomes in combination with mesenchymal stem cell transplantation in a preclinical model of myocardial infarction

2020 ◽  
Vol 15 (6) ◽  
pp. 1749-1759
Author(s):  
Shuo Wang ◽  
Liu Li ◽  
Tao Liu ◽  
Wenyan Jiang ◽  
Xitian Hu
Keyword(s):  
Myocardial Infarction ◽  
Stem Cell ◽  
Mesenchymal Stem Cell ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Intervention Strategy ◽  
Heart Tissue ◽  
Preclinical Model ◽  
Mesenchymal Stem Cell Transplantation

Aim: We aimed to investigate the protection of exogenous miR-19a/19b with bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation on cardiac function and inhibition of fibrosis in myocardial infarction (MI). Materials & methods: BM-MSC-derived exosomes were used to deliver miR-19a/19b (exo/miR-19a/19b) to the cultured cardiac HL-1 cells, and the apoptosis of cells were evaluated. Exo/miR-19a/19b and BM-MSCs were also transplanted to an in vivo MI mouse model. The recovery of cardiac function was assessed and the level of cardiac fibrosis was determined. Results: Exo/miR-19a/19b and MSCs reduced the area of cardiac fibrosis in the heart tissue in the mouse MI model. Using BM-MSC-derived exosomes as a vehicle, miR-19a/19b significantly suppressed the apoptosis of cardiac HL-1 cells. The combination of Exo/miR-19a/19b and MSC transplantation significantly enhanced the recovery of cardiac function and reduced cardiac fibrosis in the MI model. Conclusion: Our study provides an effective regenerative intervention strategy to attenuate the damage of MI.

Abstract 73: A Novel Role of E2F1 in Stress-induced Cardiac Fibrosis

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Dauren Biyashev ◽  
Chan Boriboun ◽  
Gangjian Qin
Keyword(s):  
Cardiovascular System ◽  
Cardiac Fibrosis ◽  
Cardiovascular Health ◽  
Transmembrane Protein ◽  
Ang Ii ◽  
Tgf Beta ◽  
Wild Type ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts

Rationale: E2F1 transcription factor is best known as a cell cycle regulator. Recent reports indicate the importance of E2F1 in cardiovascular system, though its exact role is not clear. TGF-beta/Smad2,3 signaling pathway, on the other hand, has been long implicated in the regulation of cardiovascular health and numerous disease, including cardiac fibrosis. Interaction between these two major pathways has been reported in the cancer settings. Objective: To identify the possible interactions between E2F1 and TGF-beta/Smad2,3 signaling pathways in cardiovascular system and determine the functional outcome of these interactions in cardiac health. Methods and Results: E2F1-/- mice developed significantly higher degree of cardiac fibrosis than wild type mice in the Angiotensin II - induced cardiac fibrosis model. The levels of phosphorylated Smad2 and Smad3 were significantly higher in the hearts of E2F1-/- mice, as well as in mouse embryonic fibroblasts derived from E2F1-/- animals. Associated expression of collagen I was significantly increased in mouse embryonic fibroblasts derived from E2F1-/- animals, and treatment with TGF-beta resulted in higher collagen deposition compared to wild type fibroblasts. Treating animals with SB 431542, chemical inhibitor of Smad2,3 signaling, obliterated the difference in the degree of cardiac fibrosis between wild type and E2F1 knockout animals in the Ang II model. We discovered that levels of syndecan-4, heparan sulfate proteoglycan transmembrane protein implicated in fibrosis and known to interact with TGF-beta are significantly increased in both E2F1-/- fibroblasts and hearts. siRNA-mediated knockdown of syndecan-4 using siRNA resulted in decreased Smad2,3 phosphorylation in E2F1-/- MEFs. Similarly, down regulation of syndecan-4 in-vivo using morpholino lead to decreased cardiac fibrosis in E2F1-/- mice in Ang II model. Conclusions: E2F1 suppresses activation of TGF-beta/Smad 2,3 pathway. The E2F1-dependent suppression of cardiac fibrosis through TGF-beta/Smad 2,3 pathway is at least partially regulated by syndecan-4.

scholarly journals Glucose-6-phosphate dehydrogenase and ferredoxin-NADP(H) reductase contribute to damage repair during the soxRS response of Escherichia coli

Microbiology ◽  
2006 ◽  
Vol 152 (4) ◽  
pp. 1119-1128 ◽  
Author(s):  
Mariana Giró ◽  
Néstor Carrillo ◽  
Adriana R. Krapp
Keyword(s):  
Escherichia Coli ◽  
Survival Rates ◽  
Multicopy Plasmid ◽  
Wild Type ◽  
Iron Sulfur Clusters ◽  
Iron Sulfur ◽  
Oxidative Challenge ◽  
Glucose 6 Phosphate Dehydrogenase

The NADP(H)-dependent enzymes glucose-6-phosphate dehydrogenase (G6PDH) and ferredoxin(flavodoxin)-NADP(H) reductase (FPR), encoded by the zwf and fpr genes, respectively, are committed members of the soxRS regulatory system involved in superoxide resistance in Escherichia coli. Exposure of E. coli cells to the superoxide propagator methyl viologen (MV) led to rapid accumulation of G6PDH, while FPR was induced after a lag period of several minutes. Bacteria expressing G6PDH from a multicopy plasmid accumulated higher NADPH levels and displayed a protracted soxRS response, whereas FPR build-up had the opposite effects. Inactivation of either of the two genes resulted in enhanced sensitivity to MV killing, while further increases in the cellular content of FPR led to higher survival rates under oxidative conditions. In contrast, G6PDH accumulation over wild-type levels of expression failed to increase MV tolerance. G6PDH and FPR could act concertedly to deliver reducing equivalents from carbohydrates, via NADP+, to the FPR acceptors ferredoxin and/or flavodoxin. To evaluate whether this electron-transport system could mediate reductive repair reactions, the pathway was reconstituted in vitro from purified components; the reconstituted system was found to be functional in reactivation of oxidatively damaged iron–sulfur clusters of hydro-lyases such as aconitase and 6-phosphogluconate dehydratase. Recovery of these activities after oxidative challenge was faster and more extensive in transformed bacteria overexpressing FPR than in wild-type cells, indicating that the reductase could sustain hydro-lyase repair in vivo. However, FPR-deficient mutants were still able to fix iron–sulfur clusters at significant rates, suggesting that back-up routes for ferredoxin and/or flavodoxin reduction might be called into action to rescue inactivated enzymes when FPR is absent.

Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages

Blood ◽  
2003 ◽  
Vol 102 (13) ◽  
pp. 4410-4412 ◽  
Author(s):  
Shiori Koseki-Kuno ◽  
Mitsunori Yamakawa ◽  
Gerhard Dickneite ◽  
Akitada Ichinose
Keyword(s):  
Molecular Pathology ◽  
Factor Xiii ◽  
Vaginal Bleeding ◽  
Critical Role ◽  
Uterine Bleeding ◽  
Bleeding Events ◽  
A Subunit ◽  
Deficient Mice ◽  
Fxiii Deficiency

AbstractTo understand the molecular pathology of factor XIII (FXIII) deficiency in vivo, its A subunit (FXIIIA)-knockout (KO) mice were functionally analyzed. Although homozygous FXIIIA female KO mice were capable of becoming pregnant, most of them died due to excessive vaginal bleeding during gestation. Abdominal incisions revealed that the uteri of the dead mice were filled with blood and that some embryos were much smaller than others within a single uterus. A series of histologic examinations of the pregnant animals suggested that massive placental hemorrhage and subsequent necrosis developed in the uteri of the FXIIIA KO mice on day 10 of gestation. This was true regardless of the genotypes of fetuses. These results are reminiscent of spontaneous miscarriage in pregnant humans with FXIII deficiency and indicate that maternal FXIII plays a critical role in uterine hemostasis and maintenance of the placenta during gestation. (Blood. 2003;102:4410-4412)

scholarly journals Listeria monocytogenes Infection in Caspase-11-Deficient Mice

2002 ◽  
Vol 70 (5) ◽  
pp. 2657-2664 ◽  
Author(s):  
Nicolas J. Mueller ◽  
Robert A. Wilkinson ◽  
Jay A. Fishman
Keyword(s):  
Immune Response ◽  
Listeria Monocytogenes ◽  
Survival Rates ◽  
Intraperitoneal Administration ◽  
Cytokine Signaling ◽  
Wild Type ◽  
Alternative Pathways ◽  
Similar Survival

ABSTRACT Caspase-11 (Cas11) is a cysteine protease involved in programmed cell death and cytokine maturation. Through activation of Cas1 (interleukin-1β [IL-1β]-converting enzyme), Cas11 is directly involved in the maturation of IL-1β and IL-18. Apoptosis is mediated through Cas3. Given the role of apoptosis and cytokine signaling during the innate immune response in intracellular infection, we examined Cas11-deficient (Cas11−/−) mice during infection with Listeria monocytogenes. Cas11−/− and wild-type C57BL/6 mice were equally susceptible to intravenous infection with L. monocytogenes, resulting in similar bacterial burdens in tissue and similar survival rates. By contrast, enhanced susceptibility was observed in control mice on a mixed genetic 129/C57BL/DBA2 background. Cas11−/− and wild-type mice infected with Listeria had similar hepatic microabscess formation in terms of histologic appearance, size, and number. Apoptosis of L. monocytogenes-infected hepatocytes in vivo and in vitro in primary culture was not altered by the absence of Cas11. Serum IL-18 and IL-1β levels were similar in Cas11−/− mice and controls. Endotoxin (lipopolysaccharide [LPS])-challenged Cas11−/− mice were deficient in the production of gamma interferon. IL-1β responses in Cas11−/− were normal with intravenous administration of LPS but decreased with intraperitoneal administration. Our findings suggest that Cas11 deficiency does not impair the immune response to infection with L. monocytogenes. Apoptosis and maturation of IL-18 and IL-1β were normal despite Cas11 deficiency. LPS-induced proinflammatory pathways are altered by the absence of Cas11. While Cas11-mediated Cas1 and Cas3 activation is crucial for cytokine maturation and apoptosis during inflammation, alternative pathways allow normal inflammatory and apoptotic responses during infection with L. monocytogenes.

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