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Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy

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Abstract

Objective Dilated cardiomyopathy (DCM) represents a large subset of patients with congestive heart failure (HF), and myocardial fibrosis has been shown to be associated with this process. Lysyl oxidase (LOX), a key enzyme, plays a potential role in the biogenesis of connective tissue matrices by catalyzing crosslinks in collagen and elastin. However, the mechanisms involved in the remodeling process during HF are not clearly understood. The present work was aimed to determine the changes in collagen phenotypes, MMPs, TIMPs, and LOX, in DCM and non-failing human hearts. Moreover, the role of TGFβ in the induction of type III collagen in cardiac fibroblast is determined. Method Protein and RNA expression were quantified by Western and RT-PCR analysis; collagen phenotypes were determined by SDS-PAGE. Results Our data demonstrated that in all DCM hearts, the collagen concentration was significantly elevated compared to that of the NF hearts associated with an increase in Type I (18%) and Type III (33%) collagen. The content of MMP-2 and MMP-9 were increased significantly in all DCM hearts compared to NF hearts. Transcriptional level of LOX, TIMP 1, and 2 were significantly upregulated in DCM hearts. In addition, a significant increase in the transcript levels of cytokines, notably IFN, IL-6, TNF-α, and TGF-β superfamily was observed in all DCM hearts. Addition of TGFβ to cardiac fibroblasts caused a dose dependent increase in type III collagen. Conclusion Altogether, our data suggest an alteration of collagen, MMPs, various cytokines and particularly, LOX participates, in part, in the remodeling of the heart leading to cardiac dysfunction and HF.

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Acknowledgments

This study was supported in part by NIH RO-1 HL27738 and HL 47794 granted to S. Sen. Author wishes to thank Mr. David Young for his skilled technical assistance. We thankfully acknowledge heart transplant team, Dr. Christine Moravec and Wendy Sweet (Transplant Tissue Core, Cleveland Clinic, Cleveland, Ohio) for providing the human hearts. The author also wishes to thank Ms. Lori Sims for her excellent secretarial support.

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Authors and Affiliations

  1. Department of Molecular Cardiology (NB 50), Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    P. Sivakumar, Sudhiranjan Gupta, Sagartirtha Sarkar & Subha Sen

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  1. P. Sivakumar
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  2. Sudhiranjan Gupta
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  3. Sagartirtha Sarkar
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  4. Subha Sen
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Correspondence to Subha Sen.

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P. Sivakumar and Sudhiranjan Gupta contributed equally to this work.

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Sivakumar, P., Gupta, S., Sarkar, S. et al. Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy. Mol Cell Biochem 307, 159–167 (2008). https://doi.org/10.1007/s11010-007-9595-2

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