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 E Weintraub, Lisandra E. de Castro Brás

Research output: Contribution to journalArticle

4 Citations (Scopus)

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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Matrix Metalloproteinase 9
Aging of materials
Stiffness
Talin
Matrix Metalloproteinases
Extracellular Matrix
Animals
Protein Deficiency
Cytoskeletal Proteins
Extracellular Matrix Proteins
Mitochondrial Proteins
Cell adhesion
Firearms
Proteome
Masks
Cardiac Myocytes
Cell Adhesion
Integrins
Proteomics
Design of experiments

Keywords

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

ASJC Scopus subject areas

  • Clinical Biochemistry

Cite this

Matrix metalloproteinase-9-dependent mechanisms of reduced contractility and increased stiffness in the aging heart. / Padmanabhan Iyer, Rugmani; Chiao, Ying Ann; Flynn, Elizabeth R.; Hakala, Kevin; Cates, Courtney A.; Weintraub, Susan E; de Castro Brás, Lisandra E.

In: Proteomics - Clinical Applications, Vol. 10, No. 1, 01.01.2016, p. 92-107.

Research output: Contribution to journalArticle

Padmanabhan Iyer, Rugmani ; Chiao, Ying Ann ; Flynn, Elizabeth R. ; Hakala, Kevin ; Cates, Courtney A. ; Weintraub, Susan E ; de Castro Brás, Lisandra E. / Matrix metalloproteinase-9-dependent mechanisms of reduced contractility and increased stiffness in the aging heart. In: Proteomics - Clinical Applications. 2016 ; Vol. 10, No. 1. pp. 92-107.
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AU - Padmanabhan Iyer, Rugmani

AU - Chiao, Ying Ann

AU - Flynn, Elizabeth R.

AU - Hakala, Kevin

AU - Cates, Courtney A.

AU - Weintraub, Susan E

AU - de Castro Brás, Lisandra E.

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AB - 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.

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