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

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

Author information

1
San Antonio Cardiovascular Proteomics Center, San Antonio, Texas; Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi;
2
Department of Pathology, University of Washington, Seattle, Washington;
3
San Antonio Cardiovascular Proteomics Center, San Antonio, Texas;
4
San Antonio Cardiovascular Proteomics Center, San Antonio, Texas; Department of Mechanical Engineering, University of Texas at San Antonio, San Antonio, Texas;
5
San Antonio Cardiovascular Proteomics Center, San Antonio, Texas; Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi; Division of Pathological Sciences, Department of Clinical Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan;
6
San Antonio Cardiovascular Proteomics Center, San Antonio, Texas; Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi; Division of Cardiology, University of Mississippi Medical Center; Jackson, Mississippi;
7
San Antonio Cardiovascular Proteomics Center, San Antonio, Texas; Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, Jackson, Mississippi; Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center; Jackson, Mississippi; and.
8
San Antonio Cardiovascular Proteomics Center, San Antonio, Texas; Department of Electrical and Computer Engineering, University of Texas at San Antonio, San Antonio, Texas yufang.jin@utsa.edu.

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 (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

PMID:
24658018
PMCID:
PMC4024719
DOI:
10.1152/ajpheart.00090.2014
[Indexed for MEDLINE]
Free PMC Article

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