T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice

Qianli Yu, Randy Vazquez, Sherma Zabadi, Ronald R Watson, Douglas F Larson

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)511-518
Number of pages8
JournalMatrix Biology
Volume29
Issue number6
DOIs
StatePublished - Jul 2010

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Fibrillar Collagens
Extracellular Matrix
Protein-Lysine 6-Oxidase
T-Lymphocytes
Lymphocytes
Gene Expression
Immune System Phenomena
Diastolic Heart Failure
Lymphocyte Activation
Helper-Inducer T-Lymphocytes
T-Cell Antigen Receptor
Mechanics
Left Ventricular Function
Cardiac Myocytes
Cardiac Output
Fibroblasts
Cytokines

Keywords

  • Diastolic function
  • Fibrosis
  • Lysyl oxidase
  • T-lymphocyte
  • Ventricular remodeling

ASJC Scopus subject areas

  • Molecular Biology

Cite this

T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice. / Yu, Qianli; Vazquez, Randy; Zabadi, Sherma; Watson, Ronald R; Larson, Douglas F.

In: Matrix Biology, Vol. 29, No. 6, 07.2010, p. 511-518.

Research output: Contribution to journalArticle

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