Differential activation of matrix metalloproteinases in heart failure with and without ventricular dilatation.
OBJECTIVE
Remodeling of extracellular matrix (ECM) is considered to contribute to progression of left ventricular (LV) remodeling and matrix metalloproteinases (MMPs) play crucial roles in regulation of ECM. Activation of MMPs is observed in systolic heart failure (SHF) and is suggested to be responsible for LV dilatation in SHF. Diastolic heart failure (DHF) that is not associated with LV dilatation is also accompanied with collagen accumulation; however, differences in ECM regulatory system, especially activation of MMPs, between SHF and DHF remain to be clarified. This study was conducted to clarify whether MMPs are activated even in DHF, and if so, to characterize the difference in activation of MMPs between SHF and DHF for identification of a target for the prevention of LV remodeling in SHF.


METHODS
To exclude effects of differences in underling cardiovascular diseases and genetic background on the comparison between DHF and SHF, we used Dahl salt-sensitive rats fed on high salt diet starting at 7 weeks of age as DHF model and at 8 weeks as SHF model, both of which our laboratory recently developed.


RESULTS
LV fibrosis progressed in the DHF and SHF model rats. MMP-2 was activated to the same degree in both rats. Activation of MMP-9 was enhanced in the DHF model rats, but the activity was more enhanced in the SHF rats. Film in situ zymography showed that enhanced gelatinolytic activity appeared only in the mid layer of the LV wall in the DHF rats and throughout the wall in the SHF rats. The distribution of gelatinolytic activity was consistent with that of expression of MMP-9 as assessed in immunohistochemical study.


CONCLUSIONS
MMP-9 rather than MMP-2 may be involved in LV dilatation in SHF and be a specific target for the prevention of LV remodeling.
Nishikawa
Nagahiro
N
Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
Yamamoto
Kazuhiro
K
Sakata
Yasushi
Y
Mano
Toshiaki
T
Yoshida
Junichi
J
Miwa
Takeshi
T
Takeda
Hiroshi
H
Hori
Masatsugu
M
Masuyama
Tohru
T
D000818:Animals; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D003971:Diastole; D018450:Disease Progression; D005355:Fibrosis; D018093:Gelatinases; D015870:Gene Expression; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000201:enzymology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D051381:Rats; D020303:Rats, Inbred Dahl; D013599:Systole; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D020257:Ventricular Remodeling
D019714:Tissue Inhibitor of Metalloproteinases; D003094:Collagen; D018093:Gelatinases; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9