MMP in the failing heart: a potential therapeutic target. Heart failure. Heart failure is a major public health problem (1% of the total population in France).
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a potential therapeutic target
Heart failure is a major public health problem (1% of the total population in France).
It is is a common sequel to many forms of heart diseases, with various causes including pulmonary disease, myocardial infarction, arrhythmias, anemia, renal failure, nephrotic syndrome, and thyroid disease.
It is a complex disease, with many phenotypes, but which displays two main characteristics: cardiac growth and cardiac remodeling.
Large left ventricular chamber, thin left ventricular wall, loss of pumping capacity.
Thick walls, small ventricular chambers, increased pumping capacity.
(Freeman et al. JCI, 2001, 107:967; Limbird and Vaughan, PNAS, 1999, 96: 7125)
The remodeling process is not only due to changes in the cardiac cells but also to changes in the extracellular matrix.
Scanning electron micrograph, longitudinal and transversal sections, showing collagen architecture in the left pig heart ventricle.(Zenat et al. Am J Physiol (2000) 279:H602)
The myocardial ECM contains fibrillar collagens (types 1 and 3) which ensure structural integrity of the adjoining myocytes and alignment which imparts mechanical support to the myocardium and govern tissue stiffness.
Disruption within the ECM network will lead to loss of a normal structural support and abnormal stress for cardiomyocytes during contraction. This will result in changes in myocardial geometry and function.
MMP-2 , MMP-9 , MMP-3, MMP-1 , MMP-13 and MT1-MMP have been identified in the human heart, and are responsible for ECM degradation.
A cause/effect relationship between MMPs and the left ventricular remodeling proces in the course of heart failure has been documented by several studies using different approaches:
- expression and activity of the cardiac MMPs in animal models of heart failure, and human failing hearts;
- studies in knocked-out and transgenic animal models;
- pharmacological studies with MMP inhibitors.
Expression and activity of the cardiac MMPs increase time-dependently, together with the progression of heart failure.
Expression and activity of MMPs in heart failure (1).
Rapid pacing in pig.
(Spinale et al. Circ.Res., 1998,82:482)
In this model, collagen content in the heart decreases.
Expression and activity of MMPs in heart failure (2).
The infarcted mouse.
In the infarcted mouse, cardiac MMPs expression is increased.
Ducharme et al. JCI, 2000, 106:55
Increased MMPs surpass TIMPs and this occurs together with an augmentation in the collagen content.
Iwanaga et al. JACC, 2002, 39:1384
DS: Dahl salt-sensitive rat
DR: Dahl salt-resistant rat
Expression and activity of MMPs in heart failure (3).
The Dahl salt-sensitive rat.
The Dahl salt-sensitive rat develops hypertension associated with a rapidly developing heart failure when it is given a diet supplied with sodiumsalt.
In the DS rats, MMP-2 activation surpasses that of TIMPs. Myocardial fibrosis appears focally.
The human failing heart.
Li et al. Circulation 1998, 98:1728
Thomas et al. Circulation 1998, 97:1708
MMP-3 and MMP-9 are increased. TIMP-1, -3 and -4 are reduced. Such an imbalance favors persistent MMP activity.
Expression and activity of MMPs in heart failure (5).
The human failing heart.
The increased content in MMPs is associated with alterations of the ECM, and fibrosis.
Total collagen was unchanged but the ratio of undenatured collagens to total soluble collagens was increased.
Expression and activity of MMPs in heart failure (6).
The human failing heart.
Support with left ventricular assist devices downregulates matrix metalloproteases, increases TIMPs and reduces collagen damage.
Li et al. Circulation 2001, 104: 1152
MMP-9 KO mouse
Infarcted control mouse
Studies with knocked out animal models (1).
MMP-9 KO mouse
In the mouse, targeted deletion of cardiac MMP-9attenuates left ventricular enlargement and collagen accumulation after experimental infarction.
At 6 months, pathological hypertrophy with disruption of the sarcomeric architecture. However, the left ventricular pressure is increased. At 12 months, the contractile function is deteriorated.
Transgenic MMP-1 heart
Studies with transgenic animal models (2).
Transgenic MMP-1 mouse
A mouse that constituvely expresses human MMP-1
Kim et al. JCI, 2000, 106:857
Direct disruption of the extracellular matrix, induced by the overexpression of MMP-1, reproduces changes observed in the progression of human heart failure: initial adaptative response followed by progressive loss of function.
1.MMPs are increased in late-stage experimental and human heart failure.
2.TIMPs are decreased in the failing human heart
3. A paradoxal end-result is increased MMPs accompanied with increased fibrosis.
Cardiac MMPs not only ensure degradation of matrix components, but also modulate collagen synthesis.: digestion of matrix components leads to the release of biological factors (TGFß, IGF, FGF, TNFalpha..) from the extracellular matrix which initiate neo-synthesis of collagens.
Cardiac fibrosis is not only anincrease in matrix collagen, but also changes in collagen type, organization and cross-links.
PD-166793 fibrosis (Park Davis/ Pfizer)
3-methyl butyric acid) does not inhibit TACE contrarily to Batimastat and Marimastat.
Pharmacological studies (1)
Effect of PD166793 in the pig exposed to rapid pacing
Spinale et al. Circ. Res. 1999, 85: 364
Effect of PD-166793
Pharmacological studies (2).
Effect of PD166793 in the rat with progressive heart failure.
Peterson et al. Circulation 2001, 103:2303
PD-166793 administration was initiated in 9 month-old rats and continued for 4 months.
PD-166793 treatment attenuates the degree of left ventricular remodeling in Spontaneously Hypersentive Heart Failure (SHHF).
CP-471,474 (Pfizer) fibrosis
A broad spectrum inhibitor
Echocardiography in the infarcted mouse
Pharmacological studies (3)
Effect of CP-471,474 in the infarcted mouse
Rohde et al. Circulation 1999, 99:3063
Pharmacological studies (4) fibrosis
Effect of CP-471,474 in the infarcted rabbit
Lindsey et al. Circulation 2002, 105:753
CP-471,474 (Pfizer) a broad spectrum inhibitor but that does not inhibit MMP-1 in rabbits which like humans, but not rodents, express MMP-1 as a major collagenase.
Our objectives in the RTN project fibrosis
2. Measurements of cardiac MMP activity and abundance in cardiac tissue fractions in the animals treated or not with MMP inhibitor;
- Fluorescent substrates and zymography;
- Echocardiographic parameters fibrosis
DR rats (11 w)
3,5 ± 0,3
43,0 ± 0,9
0,09 ± 0,01
DS rats (11 w)
3,5 ± 0,1
0,13 ± 0,01*
50,0 ± 1,4*
DR rats (15 w)
3,3 ± 0,1
0,09 ± 0,01
42,9 ± 1,7
DS rats (15 w)
4,1 ± 0,1*
0,11 ± 0,01
39,8 ± 2,3†
The Dahl salt sensitive rat model (1)
- Blood Pressure: 220 mmHg in the Dahl salt sensitive (DS) rat as young as 11 weeks, to compare with 152 mmHg in the Dahl salt resistant (DR) rat.
11 weeks fibrosis
Collagen staining with red sirius
DS 11 weeks
DR 11 weeks
Endogenous MMP activity
Collagénase activity (nU)
Age of the rats (weeks)
The Dahl salt sensitive rat model (2)
Fibrosis and MMPs
Isolated cardiomyocytes fibrosisloaded with Fura-2 , electrically stimulated and exposed to a positive inotropic agent
F360 / F380
Isolated adult rat cardiomyocytes
Immunostaining with phalloidin
Marie Claude Bourin