Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction

Andriy Yabluchanskiy, Yonggang Ma, Ying Ann Chiao, Elizabeth F. Lopez, Andrew P. Voorhees, Hiroe Toba, Michael E. Hall, Hai Chao Han, Merry L. Lindsey, Yu Fang Jin

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Aging is linked to increased matrix metalloproteinase-9 (MMP-9 expression and extracellular matrix turnover, as well as a decline in function of the left ventricle (LV. Previously, we demonstrated that C57BL/6J wild-type (WT mice > 18 mo of age show impaired diastolic function, which was attenuated by MMP-9 deletion. To evaluate mechanisms that initiate the development of cardiac dysfunction, we compared the LVs of 6-9- and 15-18-mo-old WT and MMP-9 null (Null mice. All groups showed similar LV function by echocardiography, indicating that dysfunction had not yet developed in the older group. Myocyte nuclei numbers and cross-sectional areas increased in both WT and Null 15-18-mo mice compared with young controls, indicating myocyte hypertrophy. Myocyte hypertrophy leads to an increased oxygen demand, and both WT and Null 15-18-mo mice showed an increase in angiogenic signaling. Plasma proteomic profiling and LV analysis revealed a threefold increase in von Willebrand factor and fivefold increase in vascular endothelial growth factor in WT 15-18-mo mice, which were further elevated in Null mice. In contrast to the upregulation of angiogenic stimulating factors, actual LV vessel numbers increased only in the 15-18-mo Null LV. The 15-18-mo WT showed amplified expression of inflammatory genes related to angiogenesis, including C-C chemokine receptor (CCR7, CCR10, interleukin (IL-1f8, IL-13, and IL-20 (all, P < 0.05, and these increases were blunted by MMP-9 deletion (all, P < 0.05. To measure vascular permeability as an index of endothelial function, we injected mice with FITC-labeled dextran. The 15-18-mo WT LV showed increased vascular permeability compared with young WT controls and 15-18-mo Null mice. Combined, our findings revealed that MMP-9 deletion improves angiogenesis, attenuates inflammation, and prevents vascular leakiness in the setting of cardiac aging.

Original languageEnglish (US)
Pages (from-to)H1398-H1407
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume306
Issue number10
DOIs
StatePublished - May 15 2014

Keywords

  • Aging
  • Angiogenesis
  • Extracellular matrix
  • Inflammation
  • MMP-9
  • Proteomics

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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  • Cite this

    Yabluchanskiy, A., Ma, Y., Chiao, Y. A., Lopez, E. F., Voorhees, A. P., Toba, H., Hall, M. E., Han, H. C., Lindsey, M. L., & Jin, Y. F. (2014). Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction. American Journal of Physiology - Heart and Circulatory Physiology, 306(10), H1398-H1407. https://doi.org/10.1152/ajpheart.00090.2014