Matrix metalloproteinase inhibition attenuates left ventricular remodeling and dysfunction in a rat model of progressive heart failure.
BACKGROUND
Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure.


RESULTS
LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg. kg(-1). d(-1) PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116+/-11 micromol/L) reduced in vitro LV myocardial MMP-2 activity by approximately 100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578+/-477 versus 5983+/-109 mm Hg/s, P</=0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443+/-12 versus 563+/-33 mL, P</=0.05) and increased further by 13 months (899+/-64 mL, P</=0.05). LV myocardial MMP-2 activity was increased by approximately 2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678+/-28 mL, P</=0.05).


CONCLUSIONS
MMP activity contributes to LV dilation and progression to LV dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.
Peterson
J T
JT
Departments of Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, Michigan, USA. tom.peterson@pfizer.com
Hallak
H
H
Johnson
L
L
Li
H
H
O'Brien
P M
PM
Sliskovic
D R
DR
Bocan
T M
TM
Coker
M L
ML
Etoh
T
T
Spinale
F G
FG
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000627:therapeutic use; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D006877:Hydroxamic Acids / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009842:Oligopeptides / Q000097:blood / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011920:Rats, Inbred WF; D012680:Sensitivity and Specificity; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
C370242:(R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D020782:Matrix Metalloproteinases