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Type-specific dysregulation of matrix metalloproteinases and their tissue inhibitors in end-stage heart failure patients: relationship between MMP-10 and LV remodelling.

ABSTRACT: Although past studies observed the changes of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in end-stage heart failure (HF) patients, a consistent and clear pattern of type-specific MMPs and/or TIMPs has yet to be further defined. In this study, proteomic approach of human protein antibody arrays was used to compare MMP and TIMP expression levels of left ventricular (LV) myocardial samples from end-stage HF patients due to dilated cardiomyopathy (DCM) with those from age- and sex- matched non-failing patients. Western blot analysis, immunohistochemistry and ELISA were used for validation of our results. We observed that MMP-10 and -7 abundance increased, accompanied by decreased TIMP-4 in DCM failing hearts (n= 8) compared with non-failing hearts (n= 8). The results were further validated in a cohort of 34 end-stage HF patients derived from three forms of cardiomyopathies. Cardiac and plasma MMP-10 levels were positively correlated with the LV end-diastolic dimension in this HF cohort. In addition, we observed that insulin-like growth factor-2 promoted MMP-10 production in neonatal rat cardiomyocytes. In conclusion, this study demonstrated a selective up-regulation of MMP-10 and -7 along with a discordant change of TIMP-4, and a positive correlation between MMP-10 levels and the degree of LV dilation in end-stage HF patients. Our findings suggest that type-specific dysregulation of MMPs and TIMPs is associated with LV remodelling in end-stage HF patients, and MMP-10 may act as a novel biomarker for LV remodelling.

SUBMITTER: Wei Y

PROVIDER: S-EPMC3922666 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Type-specific dysregulation of matrix metalloproteinases and their tissue inhibitors in end-stage heart failure patients: relationship between MMP-10 and LV remodelling.

Wei Yingjie Y Cui Chuanjue C Lainscak Mitja M Zhang Xiaoling X Li Jun J Huang Jie J Zhang Hao H Zheng Zhe Z Hu Shengshou S

Journal of cellular and molecular medicine 20110401 4

Although past studies observed the changes of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in end-stage heart failure (HF) patients, a consistent and clear pattern of type-specific MMPs and/or TIMPs has yet to be further defined. In this study, proteomic approach of human protein antibody arrays was used to compare MMP and TIMP expression levels of left ventricular (LV) myocardial samples from end-stage HF patients due to dilated cardiomyopathy (DCM) with ...[more]

PMID: 20219015

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Project description:AimsHeart failure is a major complication in cancer treatment due to the cardiotoxic effects of anticancer drugs, especially from the anthracyclines such as doxorubicin (DXR). DXR enhances oxidative stress and stimulates matrix metalloproteinase-2 (MMP-2) in cardiomyocytes. We investigated whether MMP inhibitors protect against DXR cardiotoxicity given the role of MMP-2 in proteolyzing sarcomeric proteins in the heart and remodelling the extracellular matrix.Methods and resultsEight-week-old male C57BL/6J mice were treated with DXR weekly with or without MMP inhibitors doxycycline or ONO-4817 by daily oral gavage for 4 weeks. Echocardiography was used to determine cardiac function and left ventricular remodelling before and after treatment. MMP inhibitors ameliorated DXR-induced systolic and diastolic dysfunction by reducing the loss in left ventricular ejection fraction, fractional shortening, and E'/A'. MMP inhibitors attenuated adverse left ventricular remodelling, reduced cardiomyocyte dropout, and prevented myocardial fibrosis. DXR increased myocardial MMP-2 activity in part also by upregulating N-terminal truncated MMP-2. Immunogold transmission electron microscopy showed that DXR elevated MMP-2 levels within the sarcomere and mitochondria which were associated with myofilament lysis, mitochondrial degeneration, and T-tubule distention. DXR-induced myofilament lysis was associated with increased titin proteolysis in the heart which was prevented by ONO-4817. DXR also increased the level and activity of MMP-2 in human embryonic stem cell-derived cardiomyocytes, which was reduced by ONO-4817.ConclusionsMMP-2 activation is an early event in DXR cardiotoxicity and contributes to myofilament lysis by proteolyzing cardiac titin. Two orally available MMP inhibitors ameliorated DXR cardiotoxicity by attenuating intracellular and extracellular matrix remodelling, suggesting their use may be a potential prophylactic strategy to prevent heart injury during chemotherapy.

Dataset Information

Type-specific dysregulation of matrix metalloproteinases and their tissue inhibitors in end-stage heart failure patients: relationship between MMP-10 and LV remodelling.

Publications

Type-specific dysregulation of matrix metalloproteinases and their tissue inhibitors in end-stage heart failure patients: relationship between MMP-10 and LV remodelling.

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