title: T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice.
abstract: Aberrant concentrations of cardiac extracellular matrix (ECM) fibrillar collagen cross-linking have been proposed to be an underlying cause of cardiac diastolic dysfunction however the role of the adaptive immune system in this process has yet to be investigated. Fibrillar collagen cross-linking is a product of the enzymatic activities of lysyl oxidase (LOX and LOXL-3) released by the cardiac fibroblast and possibly cardiac myocytes. Our hypothesis is that stimulation of the TH1 lymphocytes activates lysyl oxidase mediated ECM cross-linking and thereby alters left ventricular function. Three-month old C57BL/J female mice were treated with selective TH1 lymphocyte inducers - T-cell receptor Vβ peptides (TCR). After 6 weeks, candidate gene expression, tissue enzymatic activity, ECM composition, and left ventricular mechanics were quantified. Lymphocyte gene expression and cytokine assay revealed TH1 immune polarization with TCR administration which was associated with a 2.6-fold and 3.1-fold increase of LOX and LOXL3 gene expression, respectively, and a 55% increase in cardiac LOX enzymatic activity. The ECM cross-linked fibrillar collagen increased by 95% when compared with the control. Concurrently, there was a 33% increased ventricular stiffness, decreased cardiac output, and normal ejection fraction. These data implicate the TH1 lymphocyte in the pathogenesis of diastolic dysfunction which has potential clinical application in the pathogenesis of diastolic heart failure.
authors.affiliation: Sarver Heart Center, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Qianli
authors.initials: Q
authors.lastname: Yu
authors.forename: Randy
authors.initials: R
authors.lastname: Vazquez
authors.forename: Sherma
authors.initials: S
authors.lastname: Zabadi
authors.forename: Ronald R
authors.initials: RR
authors.lastname: Watson
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Larson
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002302:Cardiac Output / Q000502:physiology; D009202:Cardiomyopathies / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003971:Diastole / Q000276:immunology*; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D024022:Fibrillar Collagens / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression; D006321:Heart / Q000502:physiology; D054144:Heart Failure, Diastolic / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*; D016277:Ventricular Function, Left / Q000502:physiology
chemical_list: D024022:Fibrillar Collagens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D000594:Amino Acid Oxidoreductases; D008249:Protein-Lysine 6-Oxidase