title: Matrix metalloproteinase-9-dependent mechanisms of reduced contractility and increased stiffness in the aging heart.
abstract: OBJECTIVE
  Matrix metalloproteinases (MMPs) collectively degrade all extracellular matrix (ECM) proteins. Of the MMPs, MMP-9 has the strongest link to the development of cardiac dysfunction. Aging associates with increased MMP-9 expression in the left ventricle (LV) and reduced cardiac function. We investigated the effect of MMP-9 deletion on the cardiac ECM in aged animals.
  
  
  METHODS
  We used male and female middle-aged (10- to16-month old) and old (20- to 24-month old) wild-type (WT) and MMP-9 null mice (n = 6/genotype/age). LVs were decellularized to remove highly abundant mitochondrial proteins that could mask identification of relative lower abundant components, analyzed by shotgun proteomics, and proteins of interest validated by immunoblot.
  
  
  RESULTS
  Elastin microfibril interface-located protein 1 (EMILIN-1) decreased with age in WT (p < 0.05), but not in MMP-9 null. EMILIN-1 promotes integrin-dependent cell adhesion and EMILIN-1 deficiency has been associated with vascular stiffening. Talin-2, a cytoskeletal protein, was elevated with age in WT (p < 0.05), and MMP-9 deficiency blunted this increase. Talin-2 is highly expressed in adult cardiac myocytes, transduces mechanical force to the ECM, and is activated by increases in substrate stiffness. Our results suggest that MMP-9 deletion may reduce age-related myocardial stiffness, which may explain improved cardiac function in MMP-9 null animals.
  
  
  CONCLUSIONS
  We identified age-related changes in the cardiac proteome that are MMP-9 dependent, suggesting MMP-9 as a possible therapeutic target for the aging patient.
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX, USA.|Department of Physiology and Biophysics, Mississippi Center for Heart Research, Jackson, MS, USA.
authors.forename: Rugmani
authors.initials: R
authors.lastname: Padmanabhan Iyer
authors.affiliation: 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, USA.|Department of Physiology and Biophysics, Mississippi Center for Heart Research, Jackson, MS, USA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Flynn
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX, USA.|Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hakala
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX, USA.|Department of Physiology and Biophysics, Mississippi Center for Heart Research, Jackson, MS, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Cates
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX, USA.|Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Susan T
authors.initials: ST
authors.lastname: Weintraub
authors.affiliation: San Antonio Cardiovascular Proteomics Center, San Antonio, TX, USA.|Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Lisandra E
authors.initials: LE
authors.lastname: de Castro Brás
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005260:Female; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology
chemical_list: D008562:Membrane Glycoproteins; D009124:Muscle Proteins; C030340:elastin microfibril interface located protein; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Aging; Cardiac stiffness; EMILIN; Left ventricle; MMP-9; Matrix metalloproteinase; Talin