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

Am J Physiol Heart Circ Physiol. 2014 May 15;306(10):H1398-407. doi: 10.1152/ajpheart.00090.2014. Epub 2014 Mar 21.


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 (CCR)7, 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.

Keywords: MMP-9; aging; angiogenesis; extracellular matrix; inflammation; proteomics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / physiology*
  • Animals
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology*
  • Female
  • Heart / physiopathology*
  • Hypertrophy
  • Male
  • Matrix Metalloproteinase 9 / deficiency
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / physiology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Animal
  • Myocytes, Cardiac / pathology
  • Neovascularization, Physiologic / physiology*
  • Phenotype
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Remodeling / physiology


  • Matrix Metalloproteinase 9