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Thromb Haemost 2008; 99(02): 401-408
DOI: 10.1160/TH07-10-0599
Animal Models
Schattauer GmbH

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

Masayoshi Souri
1   Department of Molecular Patho-Biochemistry and Patho-Biology on Blood and Circulation, Yamagata University School of Medicine, Yamagata, Japan
,
Shiori Koseki-Kuno
1   Department of Molecular Patho-Biochemistry and Patho-Biology on Blood and Circulation, Yamagata University School of Medicine, Yamagata, Japan
,
Naoki Takeda
2   Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan
,
Mitsunori Yamakawa
3   Department of Pathology, Yamagata University School of Medicine, Yamagata, Japan
,
Yasuchika Takeishi
4   Department of Internal Medicine I, Yamagata University School of Medicine, Yamagata, Japan
,
Jay L. Degen
5   Division of Developmental Biology, Children’s Hospital Research Foundation, Cincinnati, Ohio, USA
,
Akitada Ichinose
1   Department of Molecular Patho-Biochemistry and Patho-Biology on Blood and Circulation, Yamagata University School of Medicine, Yamagata, Japan
› Author Affiliations Financial support: This study was supported in part by research grants from The Ministry of Education, Science and Culture, Japan (10470205), The Uehara Memorial Foundation (Japan), The NOVARTIS Foundation for the Promotion of Science (Japan), The Daiwa Health Foundation (Japan), The Yamanouchi Foundation for Research on Metabolic Disorders (Japan), and The National Institutes of Health (USA, HL71555 and AR49822 to JLD).
Further Information

Publication History

Received: 08 October 2007

Accepted after major revision: 28 January 2007

Publication Date:
24 November 2017 (online)

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Summary

Factor 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.

Keywords

Transglutaminase - haemostasis - wound healing - gene-targeting
 

  • References

  • 1 Ichinose A. Extracellular transglutaminase: factor XIII. Prog Exp Tumor Res 2005; 38: 192-208.
    PubMedGoogle Scholar
  • 2 Lorand L, Graham RM. Transglutaminases: crosslinking enzymes with pleiotropic functions. Nat Rev Mol Cell Biol 2003; 4: 140-156.
    CrossrefPubMedGoogle Scholar
  • 3 Muszbek L, Adany R, Szegedi G. et al. Factor XIII of blood coagulation in human monocytes. Thromb Res 1985; 37: 401-410.
    CrossrefPubMedGoogle Scholar
  • 4 Henriksson P, Becker S, Lynch G. et al. Identification of intracellular factor XIII in human monocytes and macrophages. J Clin Invest 1985; 76: 528-534.
    CrossrefPubMedGoogle Scholar
  • 5 Kiesselbach TH, Wagner RH. Demonstration of factor XIII in human megakaryocytes by a fluorescent antibody technique. Ann NY Acad Sci 1972; 202: 318-328.
    CrossrefPubMedGoogle Scholar
  • 6 Adany R, Kiss A, Muszbek L. Factor XIII: a marker of mono- and megakaryocytopoiesis. Br J Haematol 1987; 67: 167-172.
    CrossrefPubMedGoogle Scholar
  • 7 Kida M, Souri M, Yamamoto M. et al. Transcriptional regulation of cell type-specific expression of the TATA-less A subunit gene for human coagulation factor XIII. J Biol Chem 1999; 274: 6138-6147.
    CrossrefPubMedGoogle Scholar
  • 8 Ichinose A, McMullen BA, Fujikawa K. et al. Amino acid sequence of the b subunit of human factor XIII, a protein composed of ten repetitive segments. Biochemistry 1986; 25: 4633-4638.
    CrossrefPubMedGoogle Scholar
  • 9 Nagy JA, Henriksson P, McDonagh J. Biosynthesis of factor XIII B subunit by human hepatoma cell lines. Blood 1986; 68: 1272-1279.
    PubMedGoogle Scholar
  • 10 Wolpl A, Lattke H, Board PG. et al. Coagulation factor XIII A and B subunits in bone marrow and liver transplantation. Transplantation 1987; 43: 151-153.
    CrossrefPubMedGoogle Scholar
  • 11 Duckert F. Documentation of the plasma factor XIII deficiency in man. Ann NY Acad Sci 1972; 202: 190-199.
    CrossrefPubMedGoogle Scholar
  • 12 Lorand L, Losowsky MS, Miloszewski KJ. Human factor XIII: fibrin-stabilizing factor. Prog Haemost Thromb 1980; 5: 245-290.
    PubMedGoogle Scholar
  • 13 Ichinose A, Asahina T, Kobayashi T. Congenital blood coagulation factor XIII deficiency and perinatal management. Curr Drug Targets 2005; 6: 541-549.
    CrossrefPubMedGoogle Scholar
  • 14 Anwar R, Miloszewski KJ. Factor XIII deficiency. Br J Haematol 1999; 107: 468-484.
    CrossrefPubMedGoogle Scholar
  • 15 Ichinose A. Physiopathology and regulation of factor XIII. Thromb Haemost 2001; 86: 57-65.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Ivaskevicius V, Seitz R, Kohler HP. et al. International registry on factor XIII deficiency: a basis formed mostly on European data. Thromb Haemost 2007; 97: 914-921.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Capellato MG, Lazzaro AR, Marafioti F. et al. A new family with congenital factor XIII deficiency showing a deficit of both subunit A and B. Type I factor XIII deficiency. Haematologia (Budap) 1987; 20: 179-187.
    PubMedGoogle Scholar
  • 18 Saito M, Asakura H, Yoshida T. et al. A familial factor XIII subunit B deficiency. Br J Haematol 1990; 74: 290-294.
    CrossrefPubMedGoogle Scholar
  • 19 Souri M, Izumi T, Higashi Y. et al. A founder effect is proposed for factor XIII B subunit deficiency caused by the insertion of triplet AAC in exon III encoding the second Sushi domain. Thromb Haemost 1998; 80: 211-213.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Koseki S, Souri M, Koga S. et al. Truncated mutant B subunit for factor XIII causes its deficiency due to impaired intracellular transportation. Blood 2001; 97: 2667-2672.
    CrossrefPubMedGoogle Scholar
  • 21 Izumi T, Hashiguchi T, Castaman G. et al. Type I factor XIII deficiency is caused by a genetic defect of its b subunit: insertion of triplet AAC in exon III leads to premature termination in the second Sushi domain. Blood 1996; 87: 2769-2774.
    PubMedGoogle Scholar
  • 22 Lauer P, Metzner HJ, Zettlmeissl G. et al. Targeted inactivation of the mouse locus encoding coagulation factor XIII-A: haemostatic abnormalities in mutant mice and characterization of the coagulation deficit. Thromb Haemost 2002; 88: 967-974.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 23 Koseki-Kuno S, Yamakawa M, Dickneite G. et al. Factor XIII A subunit-deficient mice developed severe uterine bleeding events and subsequent spontaneous miscarriages. Blood 2003; 102: 4410-4412.
    CrossrefPubMedGoogle Scholar
  • 24 Arimoto T, Takeishi Y, Takahashi H. et al. Cardiacspecific overexpression of diacylglycerol kinase prevents Gq protein-coupled receptor agonist-induced cardiac hypertrophy in transgenic mice. Circulation 2006; 113: 60-66.
    PubMedGoogle Scholar
  • 25 Pawlinski R, Fernandes A, Kehrle B. et al. Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction. Proc Natl Acad Sci USA 2002; 99: 15333-15338.
    CrossrefPubMedGoogle Scholar
  • 26 Leinwand LA. Sex is a potent modifier of the cardiovascular system. J Clin Invest 2003; 112: 302-307.
    CrossrefPubMedGoogle Scholar
  • 27 Small K, Feng JF, Lorenz J. et al. Cardiac specific overexpression of transglutaminase II (G(h)) results in a unique hypertrophy phenotype independent of phospholipase C activation. J Biol Chem 1999; 274: 21291-21296.
    CrossrefPubMedGoogle Scholar
  • 28 Nahrendorf M, Hu K, Frantz S. et al. Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial infarction. Circulation 2006; 113: 1196-1202.
    CrossrefPubMedGoogle Scholar
  • 29 Ichinose A, Hendrickson LE, Fujikawa K. et al. Amino acid sequence of the a subunit of human factor XIII. Biochemistry 1986; 25: 6900-6906.
    CrossrefPubMedGoogle Scholar
  • 30 Mikkola H, Muszbek L, Laiho E. et al. Molecular mechanism of a mild phenotype in coagulation factor XIII (FXIII) deficiency: a splicing mutation permitting partial correct splicing of FXIII A-subunit mRNA. Blood 1997; 89: 1279-1287.
    PubMedGoogle Scholar
  • 31 Inbal A, Lubetsky A, Krapp T. et al. Impaired wound healing in factor XIII deficient mice. Thromb Haemost 2005; 94: 432-437.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Dardik R, Leor J, Skutelsky E. et al. Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice. Thromb Haemost 2006; 95: 546-550.
    Article in Thieme ConnectPubMedGoogle Scholar