Diabetes influences cardiac extracellular matrix remodelling after myocardial infarction and subsequent development of cardiac dysfunction

Megumi Eguchi,Gary Sweeney,Guoxiong Xu,Ren-Ke Li

doi:10.1111/j.1582-4934.2012.01613.x

Abstract

This study was conducted to examine the influence of acute streptozotocin-induced diabetes on cardiac remodelling and function in mice subjected to myocardial infarction (MI) by coronary artery ligation. Echocardiography analysis indicated that diabetes induced deleterious cardiac functional changes as demonstrated by the negative differences of ejection fraction, fractional shortening, stroke volume, cardiac output and left ventricular volume 24 hrs after MI. Temporal analysis for up to 2 weeks after MI showed higher mortality in diabetic animals because of cardiac wall rupture. To examine extracellular matrix remodelling, we used fluorescent molecular tomography to conduct temporal studies and observed that total matrix metalloproteinase (MMP) activity in hearts was higher in diabetic animals at 7 and 14 days after MI, which correlated well with the degree of collagen deposition in the infarct area visualized by scanning electron microscopy. Gene arrays indicated temporal changes in expression of distinct MMP isoforms after 1 or 2 weeks after MI, particularly in diabetic mice. Temporal changes in cardiac performance were observed, with a trend of exaggerated dysfunction in diabetic mice up to 14 days after MI. Decreased radial and longitudinal systolic and diastolic strain rates were observed over 14 days after MI, and there was a trend towards altered strain rates in diabetic mouse hearts with dyssynchronous wall motion clearly evident. This correlated with increased collagen deposition in remote areas of these infarcted hearts indicated by Masson's trichrome staining. In summary, temporal changes in extracellular matrix remodelling correlated with exaggerated cardiac dysfunction in diabetic mice after MI.

Highlights

It is well-established that diabetes confers an elevated risk of cardiovascular disease, including heart failure [1, 2]
The negative percentage change in ejection fraction, fractional shortening and stroke volume were significantly larger in STZ-treated mice compared with the VEH-treated control mice demonstrating a worsen cardiac dysfunction induced by diabetes (Fig. 1, *P < 0.05)
The myocardial infarction (MI) resulted in ventricular dilation in control mice, the net change in end-diastolic and end-systolic left ventricular (LV) volumes were significantly greater in STZ-treated mice compared with the VEH-treated control mice (Fig. 1, *P < 0.05)

Summary

Introduction

It is well-established that diabetes confers an elevated risk of cardiovascular disease, including heart failure [1, 2]. One important remodelling event involves changes in the synthesis and degradation of the cardiac extracellular matrix (ECM) [7, 8]. MI-induced cardiac remodelling is associated with a robust activation of matrix metalloproteinases, which degrade collagen. Numerous studies using both transgenic animals and pharmacological inhibitors have demonstrated that altered activity of matrix metalloproteinases in the heart is associated with adverse cardiac remodelling [10,11,12,13,14].

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Results

Conclusion