Activation of matrix metalloproteinase dilates and decreases cardiac tensile strength
Introduction
In the study of left ventricle dysfunction (SOLVD), the investigators demonstrated that in normal human heart, after acute ischemic injury, left ventricle (LV) wall stress increases whereas wall thickness and ejection fraction decrease. To compensate for the injury response the entire myocardium undergoes compensatory hypertrophy and remodels the entire chamber. While wall thickness is increased during compensatory response, the ejection fraction and wall stress are maintained. However, in decompensatory congestive heart failure, the wall stress increases, and ejection fraction and wall thickness decrease significantly [1]. The spontaneously hypertensive rat (SHR) is a laboratory model of naturally developing hypertension that appears to be similar in a number of respects to essential hypertension in humans [2], [3]. Previous studies in the SHR have demonstrated that in addition to LV hypertrophy there is also an increase in interstitial fibrillar collagen [4]. Structural remodeling of the extracellular matrix (ECM) has been implicated in alterations in myocardial stiffness [5], which may contribute to both systolic and diastolic dysfunction in hypertrophied hearts. Remodeling by its very nature implies synthesis and degradation of ECM, leading to alteration in the ECM composition and concentration. The matrix metalloproteinase-2 (MMP-2) which especially degrades elastin [6] as well as interstitial fibrillar collagen [7] may induce systolic and diastolic impairment. One of the causes of myocardial wall thinning during transition from compensatory hypertrophy to decompensatory heart failure is in part due to increased MMPs activity and substantial ECM degradation [8], [9]. In SHR model, persistent hypertension begins at 6–8 weeks and is followed relatively long period (24–36 weeks) of stable compensatory pressure overload hypertrophy. At ∼70 weeks male SHR develops volume overload with decompensatory heart failure [2] in which cardiac ECM is being degraded and MMPs are robustly activated [10] and the levels of tissue inhibitor of metalloproteinase-4 (TIMP-4) are abrogated [10]. Although MMPs are activated in end-stage heart failure and cardiac wall looses its tensile strength. It is not clear whether the activation of MMP is one of the causes of decreased tensile strength in failing heart. We hypothesize that activation of MMP during the development of cardiac failure leads to decrease systolic and diastolic cardiac tensile strength.
Section snippets
Experimental model of LV hypertrophy and fibrosis
Spontaneously hypertensive rats (SHR) have been shown to develop impaired myocardial function after a period (30–36 weeks) of stable hypertrophy. Trippodo and Frohlich [3] have summarized the evidence supporting the use of SHR as a genetic model of hypertension and related this model to human heart hypertrophic disease. The changes in these animals are well characterized at both the functional and morphological levels [2], [11]. Age matched genetically SHR and their control normotensive Wistar
LV hypertrophy
The heart/body ratio was: 0.0036±0.0002, 0.0038±0.0001, 0.0035±0.0003 and 0.0071±0.0001 in NWR8w, SHR8w, NWR32w and SHR32w, respectively, suggesting significant (P<0.01) LV hypertrophy in SHR at 32 weeks as compared to NWR. The LV and RV wall thickness and diameters were also increased in the SHR32wks as compared to NWR32wks (Fig. 1 and Table 1).
MMP-2 activity
To determine whether LV hypertrophy is associated with increased MMP activity, the levels of MMP-2 activity in hearts from SHR and NWR were measured by
Discussion
The mechanism of decreased cardiac tensile strength during the development of heart failure is not well understood. We demonstrated that increased MMP-2 activity and decreased elastin/collagen ratio is one of the causes of decreased ventricular tensile strength during the transition from compensatory hypertrophy to decompensatory heart failure. Similar changes were observed in RV and LV of SHR, but because the hypertrophy is primarily associated with LV dysfunction, the levels of changes in LV
Acknowledgements
The authors greatly appreciate the generous help of Dr Indria Rao and Ms Yolanda Smith in histological staining. This work was supported in part by NIH grants GM-48595, HL-51971, and AHA Mississippi Affiliate, and Kidney Care Foundation of Mississippi.
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