Matrix metalloproteinase-9-dependent mechanisms of reduced contractility and increased stiffness in the aging heart.
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.
['Padmanabhan Iyer|Rugmani|R|', 'Chiao|Ying Ann|YA|', 'Flynn|Elizabeth R|ER|', 'Hakala|Kevin|K|', 'Cates|Courtney A|CA|', 'Weintraub|Susan T|ST|', 'de Castro Brás|Lisandra E|LE|']
D000375:Aging D000818:Animals D005260:Female D008297:Male D020780:Matrix Metalloproteinase 9 D008562:Membrane Glycoproteins D051379:Mice D008817:Mice, Mutant Strains D009124:Muscle Proteins D009200:Myocardial Contraction D009206:Myocardium
Aging Matrix metalloproteinase MMP-9 Left ventricle Cardiac stiffness EMILIN Talin