title: Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence.
abstract: OBJECTIVE
  Cardiac ageing involves the progressive development of cardiac fibrosis and diastolic dysfunction coordinated by MMP-9. Here, we report a cardiac ageing signature that encompasses macrophage pro-inflammatory signalling in the left ventricle (LV) and distinguishes biological from chronological ageing.
  
  
  RESULTS
  Young (6-9 months), middle-aged (12-15 months), old (18-24 months), and senescent (26-34 months) mice of both C57BL/6J wild type (WT) and MMP-9 null were evaluated. Using an identified inflammatory pattern, we were able to define individual mice based on their biological, rather than chronological, age. Bcl6, Ccl24, and Il4 were the strongest inflammatory markers of the cardiac ageing signature. The decline in early-to-late LV filling ratio was most strongly predicted by Bcl6, Il1r1, Ccl24, Crp, and Cxcl13 patterns, whereas LV wall thickness was most predicted by Abcf1, Tollip, Scye1, and Mif patterns. With age, there was a linear increase in cardiac M1 macrophages and a decrease in cardiac M2 macrophages in WT mice; of which, both were prevented by MMP-9 deletion. In vitro, MMP-9 directly activated young macrophage polarization to an M1/M2 mid-transition state.
  
  
  CONCLUSIONS
  Our results define the cardiac ageing inflammatory signature and assign MMP-9 roles in mediating the inflammaging profile by indirectly and directly modifying macrophage polarization. Our results explain early mechanisms that stimulate ageing-induced cardiac fibrosis and diastolic dysfunction.
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.
authors.forename: Yonggang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Ying Ann
authors.initials: YA
authors.lastname: Chiao
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Clark
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Flynn
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.
authors.forename: Andriy
authors.initials: A
authors.lastname: Yabluchanskiy
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Department of Electrical and Computer Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Ghasemi
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA.
authors.forename: Fouad
authors.initials: F
authors.lastname: Zouein
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Mississippi Center for Heart Research, Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216-4505, USA Research Services, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA mllindsey@umc.edu yufang.jin@utsa.edu.
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX 78229, USA Department of Electrical and Computer Engineering, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA mllindsey@umc.edu yufang.jin@utsa.edu.
authors.forename: Yu-Fang
authors.initials: YF
authors.lastname: Jin
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002450:Cell Communication; D016922:Cellular Senescence; D003971:Diastole; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D010641:Phenotype; D015398:Signal Transduction; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D018836:Inflammation Mediators; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Cardiac ageing; Inflammation; MMP-9; Macrophage polarization; Proteomics