Matrix metalloproteinase-9-dependent mechanisms of reduced contractility and increased stiffness in the aging heart

Proteomics Clin Appl. 2016 Jan;10(1):92-107. doi: 10.1002/prca.201500038. Epub 2015 Dec 17.


Purpose: 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.

Experimental design: 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.

Keywords: Aging; Cardiac stiffness; EMILIN; Left ventricle; MMP-9; Matrix metalloproteinase; Talin.

Publication types

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

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Aging / pathology
  • Animals
  • Female
  • Male
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Mutant Strains
  • Muscle Proteins / genetics
  • Muscle Proteins / metabolism*
  • Myocardial Contraction*
  • Myocardium / metabolism*
  • Myocardium / pathology


  • Membrane Glycoproteins
  • Muscle Proteins
  • elastin microfibril interface located protein
  • Matrix Metalloproteinase 9
  • Mmp9 protein, mouse