Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy.
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 TGFbeta in the induction of type III collagen in cardiac fibroblast is determined.


METHODS
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-alpha, and TGF-beta superfamily was observed in all DCM hearts. Addition of TGFbeta to cardiac fibroblasts caused a dose dependent increase in type III collagen.


CONCLUSIONS
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.
Sivakumar
P
P
Department of Molecular Cardiology (NB 50), Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Gupta
Sudhiranjan
S
Sarkar
Sagartirtha
S
Sen
Subha
S
D002311:Cardiomyopathy, Dilated / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006333:Heart Failure / Q000201:enzymology / Q000235:genetics; D006801:Humans; D020782:Matrix Metalloproteinases / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000235:genetics*
D016207:Cytokines; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D003094:Collagen; D008249:Protein-Lysine 6-Oxidase; D020782:Matrix Metalloproteinases