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

Rugmani Padmanabhan Iyer, Ying Ann Chiao, Elizabeth R. Flynn, Kevin Hakala, Courtney A. Cates, Susan T. Weintraub, Lisandra E. de Castro Brás

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)92-107
Number of pages16
JournalProteomics - Clinical Applications
Volume10
Issue number1
DOIs
StatePublished - Jan 1 2016

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Keywords

  • Aging
  • Cardiac stiffness
  • EMILIN
  • Left ventricle
  • MMP-9
  • Matrix metalloproteinase
  • Talin

ASJC Scopus subject areas

  • Clinical Biochemistry

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