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Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy.

ABSTRACT: Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to nonfailing hearts. We then isolated the extracellular matrix from a subset of these hearts and performed a proteomic analysis on the isolated matrices. We found that the levels of 26 structural proteins were altered in the DCM-failing isolated cardiac extracellular matrix compared to nonfailing isolated cardiac extracellular matrix. Overall, most of the extracellular matrix proteins showed reduced levels in the DCM-failing hearts, while all of the contractile proteins showed increased levels. There was a mixture of increased and decreased levels of cytoskeletal and nuclear transport proteins. Using immunoprobing, we verified that collagen IV (?2 and ?6 isoforms), zyxin, and myomesin protein levels were reduced in the DCM-failing hearts. We expect that these data will add to the understanding of the pathology associated with heart failure with DCM.

SUBMITTER: DeAguero JL

PROVIDER: S-EPMC5494967 | biostudies-literature | 2017 Jan - Feb

REPOSITORIES: biostudies-literature

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Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy.

DeAguero Joshua L JL McKown Elizabeth N EN Zhang Liwen L Keirsey Jeremy J Fischer Edgar G EG Samedi Von G VG Canan Benjamin D BD Kilic Ahmet A Janssen Paul M L PM Delfín Dawn A DA

Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology 20161015

Dilated cardiomyopathy (DCM) is associated with extensive pathological cardiac remodeling and involves numerous changes in the protein expression profile of the extracellular matrix of the heart. We obtained seven human, end-stage, failing hearts with DCM (DCM-failing) and nine human, nonfailing donor hearts and compared their extracellular matrix protein profiles. We first showed that the DCM-failing hearts had indeed undergone extensive remodeling of the left ventricle myocardium relative to n ...[more]

PMID: 27837684

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Project description:Background Dilated cardiomyopathy (DCM) is a common cause of heart failure in adult and pediatric patients, but the underlying mechanism may vary in adults and children, with few studies conducted to date. The objective of the present study was to determine whether differential remodeling of the extracellular matrix contributes to the differences between pediatric and adult DCM hearts. Methods and Results Explanted hearts were procured from adult (age, 46-61 years) and pediatric (age, 2-8) patients with DCM-related heart failure and nonfailing control hearts. Fibrillar and nonfibrillar extracellular matrix (proteoglycans, glycosaminoglycans, glycoprotein), their regulatory enzymes (matrix metalloproteinases, disintegrin and metalloproteinases, and disintegrin and metalloproteinases with a thrombospondin domain), and their inhibitors (tissue inhibitor of metalloproteinases) were assessed. Pediatric DCM hearts exhibited less fibrosis compared with adult DCMs. Total glycosaminoglycans increased similarly in both DCM groups but exhibited a significantly lower affinity for transforming growth factor-β in adult DCMs versus pediatric DCMs, resulting in increased bioavailability of transforming growth factor-β1 and a significantly higher activity of the Smad2/3 pathway in adult DCMs. Glycosylated biglycan and versican, and cleaved thrombospondin-1 increased in both DCMs. Protein expression of disintegrin and metalloproteinases with thrombospondin domains (-1, -2, -4, -7) and disintegrin and metalloproteinases (-12, -15, -17, -19) were altered differently in pediatric and adult control and failing hearts. Total matrix metalloproteinase activity increased in both DCMs. Tissue inhibitor of metalloproteinase levels were altered similarly with heart failure in both age groups, and only tissue inhibitor of metalloproteinase 3 decreased in both DCM groups. Conclusions Differential remodeling of glycosaminoglycans in pediatric DCMs versus adult DCMs could underlie the enhanced activation of the transforming growth factor-β pathway, leading to more fibrosis in adult DCM hearts. The distinct remodeling of the fibrillar and nonfibrillar extracellular matrix between pediatric and adult DCM hearts highlights a distinct pathophysiological basis for these cohorts.

Dataset Information

Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy.

Publications

Altered protein levels in the isolated extracellular matrix of failing human hearts with dilated cardiomyopathy.

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