Abstract
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.
We’re sorry, something doesn't seem to be working properly.
Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.
References
Owan, T. E., Hodge, D. O., Herges, R. M., Jacobsen, S. J., Roger, V. L., & Redfield, M. M. (2006). Trends in prevalence and outcome of heart failure with preserved ejection fraction. The New England Journal of Medicine, 355, 251–259.
Kass, D. A., Bronzwaer, J. G. F., & Paulus, W. J. (2004). What mechanisms underlie diastolic dysfunction in heart failure? Circulation Research, 94, 1533–1542.
Zile, M. R., Baicu, C. F., & Gaasch, W. H. (2004). Diastolic heart failure—Abnormalities in active relaxation and passive stiffness of the left ventricle. The New England Journal of Medicine, 350, 1953–1959.
Badenhorst, D., Maseko, M., Tsotetsi, O. J., Naidoo, A., Brooksbank, R., Norton, G. R., et al. (2003). Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats. Cardiovascular Research, 57, 632–641.
Smith-Mungo, L. I., & Kagan, H. M. (1998). Lysyl oxidase: Properties, regulation and multiple functions in biology. Matrix Biology, 16, 387–398.
Yndestad, A., Ueland, T., Oie, E., Florholmen, G., Halvorsen, B., Attramadal, H., et al. (2004). Elevated levels of activin a in heart failure—Potential role in myocardial remodeling. Circulation, 109, 1379–1385.
Yu, Q. L., Watson, R. R., Marchalonis, J. J., & Larson, D. F. (2005). A role for T lymphocytes in mediating cardiac diastolic function. American journal of physiology Heart and circulatory physiology, 289, H643–H651.
Yu, Q. L., Horak, K., & Larson, D. F. (2006). Role of T lymphocytes in hypertension-induced cardiac extracellular matrix remodeling. Hypertension, 48, 98–104.
Zibadi, S., Yu, Q., Rohdewald, P. J., Larson, D. F., & Watson, R. R. (2007). Impact of Pycnogenol (R) on cardiac extracellular matrix remodeling induced by L-NAME administration to old mice. Cardiovascular Toxicology, 7, 10–18.
Yang, B., Larson, D. F., Beischel, J., Kelley, R., Shi, J., & Watson, R. R. (2001). Validation of conductance catheter system for quantification of murine pressure-volume loops. International journal of surgical investigation, 14, 341–355.
Palamakumbura, A. H., & Trackman, P. C. (2002). A fluorometric assay for detection of lysyl oxidase enzyme activity in biological samples. Analytical Biochemistry, 300, 245–251.
Zibadi, S., Vazquez, R., Moore, D., Larson, D. F., & Watson, R. R. (2009). Myocardial lysyl oxidase regulation of cardiac remodeling in a murine model of diet-induced metabolic syndrome. American journal of physiology Heart and circulatory physiology, 297, H976–H982.
Smith-Mungo, L. I., & Kagan, H. M. (1998). Lysyl oxidase: Properties, regulation and multiple functions in biology. Matrix Biology, 16, 387–398.
Lopez, B., Querejeta, R., Gonzalez, A., Beaumont, J., Larman, M., & Diez, J. (2009). Impact of treatment on myocardial lysyl oxidase expression and collagen cross-linking in patients with heart failure. Hypertension, 53, U236–U253.
Kellar, R. S., Shepherd, B. R., Larson, D. F., Naughton, G. K., & Williams, S. K. (2005). Cardiac patch constructed from human fibroblasts attenuates reduction in cardiac function after acute infarct. Tissue engineering, 11, 1678–1687.
Song, Y. L., Ford, J. W., Gordon, D., & Shanley, C. J. (2000). Regulation of lysyl oxidase by interferon-gamma in rat aortic smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 982–988.
Tan, R. S. P., Taniguchi, T., & Harada, H. (1996). Identification of the lysyl oxidase gene as a target of the antioncogene transcription factor, IRF-1, and its possible role in tumor suppression. Cancer Research, 56, 2417–2421.
Shanley, C. J., GharaeeKermani, M., Sarkar, R., Welling, T. H., Kriegel, A., Ford, J. W., et al. (1997). Transforming growth factor-beta(1) increases lysyl oxidase enzyme activity and mRNA in rat aortic smooth muscle cells. Journal Vascular Surgery, 25, 446–452.
Rodriguez, C., Alcudia, J. F., Martinez-Gonzalez, J., Raposo, B., Navarro, M. A., & Badimon, L. (2008). Lysyl oxidase (LOX) down-regulation by TNF alpha: A new mechanism underlying TNF alpha-induced endothelial dysfunction. Atherosclerosis, 196, 558–564.
Hofnagel, O., Luechtenborg, B., Stolle, K., Lorkowski, S., Eschert, H., Plenz, G., et al. (2004). Proinflammatory cytokines regulate LOX-1 expression in vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 1789–1795.
Yu, Q. L., & Larson, D. F. (2007). Toll-like receptor induced il-12 and il-18 mediates cardiac ECM remodeling mediated by lysyl oxidase. Journal of Cardiac Failure, 13, 98.
Garrigue-Antar, L., Hartigan, N., & Kadler, K. E. (2002). Post-translational modification of bone morphogenetic protein-1 is required for secretion and stability of the protein. Journal Biological Chemistry, 277, 43327–43334.
Bock, O., Hoftmann, J., Theophile, K., Hussein, K., Wiese, B., Schlue, J., et al. (2008). Bone morphogenetic proteins are overexpressed in the bone marrow of primary myelofibrosis and are apparently induced by fibrogenic cytokines. American Journal of Pathology, 172, 951–960.
Li, Y. Y., McTiernan, C. F., & Feldman, A. M. (2000). Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovascular Research, 46, 214–224.
Messerli, F. H. (2004). TIMPs, MMPs and cardiovascular disease. European Heart Journal, 25, 1475–1476.
Brown, R. D., Jones, G. M., Laird, R. E., Hudson, P., & Long, C. S. (2007). Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts. Biochemical and Biophysical Research Communications, 362, 200–205.
Siwik, D. A., Chang, D. L. F., & Colucci, W. S. (2000). Interleukin-1 beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circulation Research, 86, 1259–1265.
Acknowledgments
This study was supported in part by grants from NCCAM R21 AT004177 and Wallace Research Foundation to RRW, and R01 HL079206 from NIH to DFL. The authors would like to thank to Felina Cordova and Gayle Bentley at the University of Arizona for their assistance in this project.
Conflict of interest statement
The authors declared no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Zibadi, S., Vazquez, R., Larson, D.F. et al. T Lymphocyte Regulation of Lysyl Oxidase in Diet-Induced Cardiac Fibrosis. Cardiovasc Toxicol 10, 190–198 (2010). https://doi.org/10.1007/s12012-010-9078-7
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12012-010-9078-7