title: Hyaluronidase 2 Deficiency Causes Increased Mesenchymal Cells, Congenital Heart Defects, and Heart Failure.
abstract: BACKGROUND
  Hyaluronan (HA) is required for endothelial-to-mesenchymal transition and normal heart development in the mouse. Heart abnormalities in hyaluronidase 2 (HYAL2)-deficient (Hyal2-/-) mice and humans suggested removal of HA is also important for normal heart development. We have performed longitudinal studies of heart structure and function inHyal2-/-mice to determine when, and how, HYAL2 deficiency leads to these abnormalities.
  
  
  RESULTS
  Echocardiography revealed atrial enlargement, atrial tissue masses, and valvular thickening at 4 weeks of age, as well as diastolic dysfunction that progressed with age, inHyal2-/-mice. These abnormalities were associated with increased HA, vimentin-positive cells, and fibrosis inHyal2-/-compared with control mice. Based on the severity of heart dysfunction, acute and chronic groups ofHyal2-/-mice that died at an average of 12 and 25 weeks respectively, were defined. Increased HA levels and mesenchymal cells, but not vascular endothelial growth factor inHyal2-/-embryonic hearts, suggest that HYAL2 is important to inhibit endothelial-to-mesenchymal transition. Consistent with this, in wild-type embryos, HYAL2 and HA were readily detected, and HA levels decreased with age.
  
  
  CONCLUSIONS
  These data demonstrate that disruption of normal HA catabolism inHyal2-/-mice causes increased HA, which may promote endothelial-to-mesenchymal transition and proliferation of mesenchymal cells. Excess endothelial-to-mesenchymal transition, resulting in increased mesenchymal cells, is the likely cause of morphological heart abnormalities in both humans and mice. In mice, these abnormalities result in progressive and severe diastolic dysfunction, culminating in heart failure.
authors.affiliation: From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children's Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.).
authors.forename: Biswajit
authors.initials: B
authors.lastname: Chowdhury
authors.affiliation: From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children's Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.).
authors.forename: Bo
authors.initials: B
authors.lastname: Xiang
authors.affiliation: From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children's Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.).
authors.forename: Michelle
authors.initials: M
authors.lastname: Liu
authors.affiliation: From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children's Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.).
authors.forename: Richard
authors.initials: R
authors.lastname: Hemming
authors.affiliation: From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children's Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.).
authors.forename: Vernon W
authors.initials: VW
authors.lastname: Dolinsky
authors.affiliation: From the Department of Biochemistry and Medical Genetics (B.C., M.L., R.H., B.T.-R.), Department of Pharmacology and Therapeutics (B.X., V.W.D.), and Department of Obstetrics and Gynecology (M.L.), University of Manitoba, Winnipeg, Canada; and The Children's Hospital Research Institute of Manitoba, Winnipeg, Canada (V.W.D., B.T.-R.). barbara.triggs-raine@umanitoba.ca.
authors.forename: Barbara
authors.initials: B
authors.lastname: Triggs-Raine
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation; D018450:Disease Progression; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis; D058851:GPI-Linked Proteins / Q000172:deficiency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006349:Heart Valve Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D006820:Hyaluronic Acid / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000172:deficiency* / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000201:enzymology* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction; D010641:Phenotype; D013318:Stroke Volume; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left
chemical_list: D058851:GPI-Linked Proteins; D006820:Hyaluronic Acid; C469221:Hyal2 protein, mouse; D006821:Hyaluronoglucosaminidase
keywords: cor triatriatum; developmental biology; endocardium; extracellular matrix; live birth