Activation of matrix metalloproteinase dilates and decreases cardiac tensile strength

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Abstract

Previous studies demonstrated that transition from compensatory pressure overload hypertrophy to decompensatory volume overload heart failure is associated with decreased cardiac tensile strength and activation of matrix metalloproteinase (MMP) in spontaneously hypertensive rat (SHR). To test the hypothesis that in the absence of nitric oxide activation of MMP during cardiac failure causes disruption in the organization of extracellular matrix (ECM) and leads to decrease systolic and diastolic cardiac tensile strength, we employed SHR of 24–32 weeks, which demonstrates significant cardiac hypertrophy and fibrosis. The normotensive Wistar rats (NWR) were used as control. To determine whether cardiac hypertrophy is associated with increased elastinolytic matrix metalloproteinase-2 (MMP-2) activity; quantitative elastin-zymography was performed on cardiac tissue homogenates. The MMP-2 activity was normalized by the levels of actin. The MMP-2/actin ratio was 2.0±0.5 in left ventricle (LV) and 1.5±0.25 in right ventricle (RV) of SHR32wks; and 0.5±0.25 in LV and 0.25±0.12 in RV of NWR32wks (P<0.02 when SHR compared with NWR). To measure passive diastolic cardiac function, rings from LV as well as RV through transmyocardial wall from male SHR and NWR of 6–8 weeks and 24–36 weeks were prepared. The LV wall thickness from endocardium to epicardium was 3.75±0.25 mm in SHR32wks as compared to 2.25±0.50 mm in NWR32wks (P<0.01). The ring was placed in tissue myobath and length–tension relationships were assessed. The pressure–length relationship was shifted to left in SHR as compared to NWR. The amounts of cardiac elastin and collagen were determined spectrophotometrically by measuring desmosine–isodesmosine and hydroxyproline contents, respectively. A negative correlation between elastic tensile strength and elastin/collagen ratio was elucidated. To create situation analogous to heart failure and MMP activation, we treated cardiac rings with active MMP-2 and length–tension relation was measured. The relationship was shifted to right in both SHR and NWR when compared to their respective untreated groups. The results suggested that activation of MMP led to decreased cardiac tissue tensile strength and may cause systolic and diastolic dysfunction.

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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