Age-dependent changes in myocardial matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles and fibroblast function.
OBJECTIVE
To evaluate the effects of aging on left ventricular (LV) geometry, collagen levels, matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) abundance, and myocardial fibroblast function.


METHODS
Young (3-month-old; n=28), middle-aged (MA; 15-month-old; n=17), and old (23-month-old; n=16) CB6F1 mice of both sexes were used in this study. Echocardiographic parameters were measured; collagen, MMP, and TIMP levels were determined for both the soluble and insoluble protein fractions; and fibroblast function was evaluated.


RESULTS
LV end-diastolic dimensions and wall thickness increased in both MA and old mice, accompanied by increased soluble protein and decreased insoluble collagen. Immunoblotting revealed differential MMP/TIMP profiles. Compared to MA levels, MMP-3, MMP-8, MMP-9, MMP-12, and MMP-14 increased, and TIMP-3 and TIMP-4 decreased in the insoluble fraction of old mice, suggesting increased extracellular matrix (ECM) degradative capacity. Fibroblast proliferation was blunted with age.


CONCLUSIONS
This study, for the first time, identified specific differences in cellular and extracellular processes that likely contribute to age-dependent ECM remodeling.
Lindsey
Merry L
ML
Division of Cardiothoracic Surgery Research, Room 629, Strom Thurmond Research Building, 770 MUSC Complex, Medical University of South Carolina, Charleston, SC 29425, USA. lindsem1@musc.edu
Goshorn
Danielle K
DK
Squires
Christina E
CE
Escobar
G Patricia
GP
Hendrick
Jennifer W
JW
Mingoia
Joseph T
JT
Sweterlitsch
Sarah E
SE
Spinale
Francis G
FG
D000375:Aging / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D004562:Electrocardiography; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D015151:Immunoblotting; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000032:analysis; D020784:Matrix Metalloproteinase 8 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000032:analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000502:physiology; D000097792:Tissue Inhibitor of Metalloproteinase-4
D003094:Collagen; D019278:Matrix Metalloproteinase 3; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D019717:Tissue Inhibitor of Metalloproteinase-3; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4