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(Circulation. 2001;103:2303.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure
From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
Correspondence to Dr J.T. Peterson, Cardiovascular Pharmacology, Pfizer Global Research and Development, 2800 Plymouth Rd, Ann Arbor, MI 48105. E-mail tom.peterson{at}pfizer.com
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.
Methods and 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 µmol/L) reduced in vitro LV myocardial
MMP-2 activity by 
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,
P0.05) and increased further
by 13 months (899±64 mL,
P0.05). LV myocardial MMP-2
activity was increased by 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,
P0.05).
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.
Key Words: ventricles • remodeling • hypertrophy • hypertension • systole
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Y. Takimoto, T. Aoyama, Y. Iwanaga, T. Izumi, Y. Kihara, D. Pennica, and S. Sasayama Increased expression of cardiotrophin-1 during ventricular remodeling in hypertensive rats Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H896 - H901. [Abstract] [Full Text] [PDF]
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M. L. Lindsey, J. Gannon, M. Aikawa, F. J. Schoen, E. Rabkin, L. Lopresti-Morrow, J. Crawford, S. Black, P. Libby, P. G. Mitchell, et al. Selective Matrix Metalloproteinase Inhibition Reduces Left Ventricular Remodeling but Does Not Inhibit Angiogenesis After Myocardial Infarction Circulation, February 12, 2002; 105(6): 753 - 758. [Abstract] [Full Text] [PDF]
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A. L. Chancey, G. L. Brower, J. T. Peterson, and J. S. Janicki Effects of Matrix Metalloproteinase Inhibition on Ventricular Remodeling Due to Volume Overload Circulation, April 23, 2002; 105(16): 1983 - 1988. [Abstract] [Full Text] [PDF]
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