CytoskeletonP614Activity and expression profiling of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the hearts with doxorubicin-induced cardiomyopathy

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Abstract

Purpose

Abnormal metabolism of extracellular matrix (ECM) has been proposed to participate in the structure remodeling during the progressive development of several heart diseases, such as cardiomyopathy and heart failure. ECM metabolism is tightly controlled by collagen-degrading matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). Various evidences have shown that several cardiovascular diseases are associated with an imbalance of MMPs and TIMPs expression. In the present study, we utilized doxorubicin (Dox) to induce cardiomyopathy and examined the dynamic changes of myocardial MMPs and TIMPs activity and expression during progressive cardiomyopathy.

Methods

The female C57BL/6J mice were intraperitoneal injected with 4 mg/kg of Dox weekly until reaching the accumulated dosage of 20 mg/kg. The serum and left ventricle (LV) of animals were isolated at week 1, 3, 5, 7, 9 and 12 after the first injection. The serums were applied to determine the concentration of atrial natriuretic peptide and brain natriuretic peptide. The tissues were applied to examine the enzyme activity, and gene or protein expression profiles of MMPs (MMP-1, -2, and -9) and TIMPs (TIMP-1, -2, -3, and -4).

Results

According to the physiological results of decreasing body weigh, prolonged QT interval, and increasing atrial natriuretic peptide and brain natriuretic peptide in the serum, indicated the effects of Dox cardiotoxicity in the experimental mice. At protein expression level, total MMP-1 was not influenced by Dox treatment but active form of MMP-1 (act-MMP-1) was progressively and significantly increased over time of Dox treatment. The increased MMP-2 and MMP-9 activity was detected at beginning two weeks after Dox treatment, and then both activities during end stage were significantly reduced. In contrast to gelatinase, the TIMP-2 and TIMP-4 activities during the end stage of Dox-induced cardiomyopathy were significantly increased.

Conclusion

We demonstrated a time-dependent alteration of MMPs and TIMPs in the hearts with Dox-induced cardiomyopathy. Several notable findings were discovered, including gradual increase of ventricular MMP-1 activation, reduction of expression and activity of MMP-2 and MMP-9, and induction of TIMPs activity during the progressive cardiomyopathy. These changes on the myocardial MMPs and TIMPs activity and expression may provide insight into the mechanism of cardiac remodeling in progressive cardiomyopathy.

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