T lymphocyte regulation of lysyl oxidase in diet-induced cardiac fibrosis.
Left ventricular diastolic dysfunction is an important predictor of prognosis and mortality of heart failure. Increased left ventricular stiffness can be associated with excessive myocardial fibrosis and increased cross-linked collagen by the enzyme lysyl oxidase (LOX). These cardiac extracellular matrix (ECM) remodeling processes are affected by T-lymphocyte function and phenotype. We sought to examine the role of T lymphocytes in myocardial LOX regulation in diet-induced fibrotic hearts. Female SCID mice, devoid of functional T lymphocytes, and wild-type (WT) C57BL/6 were treated with a high-fat high-simple carbohydrate (HFHSC) diet for 12 months. HFHSC-fed WT mice demonstrated a significant increase in the catalytic activity of myocardial LOX compared with respective controls. These changes coincided with a marked increase in ECM collagen cross-linking and impaired diastolic filling pattern. However, induction of LOX was minimal in the SCID mice compared with the WT group. Correspondingly fibrillar cross-linked collagen concentrations and diastolic dysfunction were less prominent in the SCID mice compared with the WT group. Our results suggest a role for T lymphocytes in this dietary induction of diastolic dysfunction through modulation of LOX-dependent collagen maturation.
Zibadi
Sherma
S
Sarver Heart Center, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA.
Vazquez
Randy
R
Larson
Douglas F
DF
Watson
Ronald R
RR
D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000187:drug effects / Q000648:ultrastructure; D005260:Female; D005355:Fibrosis; D015870:Gene Expression / Q000187:drug effects; D006331:Heart Diseases / Q000201:enzymology* / Q000209:etiology* / Q000473:pathology; D006439:Hemodynamics / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D012313:RNA / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000502:physiology*
D016207:Cytokines; D012313:RNA; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D020782:Matrix Metalloproteinases