title: Cardiac aging is initiated by matrix metalloproteinase-9-mediated endothelial dysfunction.
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.
authors.affiliation: 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;
authors.forename: Andriy
authors.initials: A
authors.lastname: Yabluchanskiy
authors.affiliation: 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;
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington;
authors.forename: Ying Ann
authors.initials: YA
authors.lastname: Chiao
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, Texas;
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Lopez
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, Texas; Department of Mechanical Engineering, University of Texas at San Antonio, San Antonio, Texas;
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Voorhees
authors.affiliation: 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;
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.affiliation: 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;
authors.forename: Michael E
authors.initials: ME
authors.lastname: Hall
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, Texas; Department of Mechanical Engineering, University of Texas at San Antonio, San Antonio, Texas;
authors.forename: Hai-Chao
authors.initials: HC
authors.lastname: Han
authors.affiliation: 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.
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
authors.affiliation: 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.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Jin
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D006321:Heart / Q000503:physiopathology*; D006984:Hypertrophy; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010641:Phenotype; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D020780:Matrix Metalloproteinase 9
keywords: MMP-9; aging; angiogenesis; extracellular matrix; inflammation; proteomics