title: Discoidin domain receptor 2 germline gene deletion leads to altered heart structure and function in the mouse.
abstract: Discoidin domain receptor 2 (DDR2) is a fibrillar collagen receptor that is expressed in mesenchymal cells throughout the body. In the heart, DDR2 is selectively expressed on cardiac fibroblasts. We generated a germline DDR2 knockout mouse and used this mouse to examine the role of DDR2 deletion on heart structure and function. Echocardiographic measurements from null mice were consistent with those from a smaller heart, with reduced left ventricular chamber dimensions and little change in wall thickness. Fractional shortening appeared normal. Left ventricular pressure measurements revealed mild inotropic and lusitropic abnormalities that were accentuated by dobutamine infusion. Both body and heart weights from 10-wk-old male mice were ~20% smaller in null mice. The reduced heart size was not simply due to reduced body weight, since cardiomyocyte lengths were atypically shorter in null mice. Although normalized cardiac collagen mass (assayed by hydroxyproline content) was not different in null mice, the collagen area fraction was statistically higher, suggesting a reduced collagen density from altered collagen deposition and cross-linking. Cultured cardiac fibroblasts from null mice deposited collagen at a slower rate than wild-type littermates, possibly due to the expression of lower prolyl 4-hydroxylase α-isoform 1 enzyme levels. We conclude that genetic deletion of the DDR2 collagen receptor alters cardiac fibroblast function. The resulting perturbations in collagen deposition can influence the structure and function of mature cardiomyocytes.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, California rcowling@ucsd.edu.
authors.forename: Randy T
authors.initials: RT
authors.lastname: Cowling
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, California.
authors.forename: Seon Ju
authors.initials: SJ
authors.lastname: Yeo
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, California.
authors.forename: In Jai
authors.initials: IJ
authors.lastname: Kim
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, California.
authors.forename: Joong Il
authors.initials: JI
authors.lastname: Park
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, California.
authors.forename: Yusu
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, California.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Dalton
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, California.
authors.forename: Kirk L
authors.initials: KL
authors.lastname: Peterson
authors.affiliation: Division of Cardiology, Department of Medicine, University of California-San Diego, La Jolla, California.
authors.forename: Barry H
authors.initials: BH
authors.lastname: Greenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D000070818:Discoidin Domain Receptors; D004280:Dobutamine / Q000494:pharmacology; D004452:Echocardiography; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006352:Heart Ventricles / Q000033:anatomy & histology* / Q000187:drug effects; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D058628:Myofibroblasts / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011975:Receptors, Mitogen / Q000235:genetics / Q000378:metabolism*; D016276:Ventricular Function
chemical_list: D011975:Receptors, Mitogen; D004280:Dobutamine; D003094:Collagen; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases
keywords: cardiac; collagen deposition; collagen receptor; development; fibroblast