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 (α2 and α6 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.

Plasma levels of microRNA-21, -126 and -423-5p alter during clinical improvement and are associated with the prognosis of acute heart failure

“…with the prognosis of acute heart failure reported by Qiang et al (8), Fukushima et al (9), Fan et al (14), Goren et al (15) and Tijsen et al (16), and considering that episodes of ADHF are associated with transient increases in the blood levels of markers of cardiac myocyte injury, extracellular matrix turnover, and inflammation (17)(18)(19), possibly reflecting an acceleration of pathological myocardial remodeling (20), it was decided to measure the plasma levels of miR-21, -126 and -423-5p in patients with ADHF at the time of hospital admission to determine whether they alter during clinical improvement. The present study additionally investigated whether the levels of these three miRs were associated with all-cause mortality for a longer follow-up period (up to 48 months).…”

Impaired adhesion of induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) to isolated extracellular matrix from failing hearts

“…Failing human heart tissues were procured as explants from patients with end-stage heart failure receiving a transplant. Details of clinical and histological data related to the nonfailing and failing heart tissues used in this study can be found in ( DeAguero et al., 2017 ). We focused on the three nonfailing and DCM-failing human hearts that were used to generate the proteomics data in ( DeAguero et al., 2017 ).…”

“…Decellularized tissue was flash frozen and lyophilized. Complete decellularization was confirmed by Masson's trichrome staining of ECM tissue sections ( DeAguero et al., 2017 ).…”

“…The pathologically remodeled ECM has altered biochemical and biophysical properties compared to healthy tissue ( Fan et al., 2012 ; Kong et al., 2014 ; Rienks et al., 2014 ; Segura et al., 2014 ; Yabluchanskiy et al., 2013 ). We have shown that the global protein content in the ECM of failing human hearts with dilated cardiomyopathy (DCM-failing) is significantly changed ( DeAguero et al., 2017 ), while others have documented changes in specific proteins ( Marijianowski et al., 1995 ). Alterations in the remodeled ECM are associated with detrimental effects on the cells that adhere to or reside within it ( Rienks et al., 2014 ).…”

Ups and downs in heart failure: the case of proteomics

“…Several studies have hitherto been published concerning, among other issues, protein alterations in conditions such as dilated cardiomyopathy, myocardial hypertrophy, atherosclerosis, atrial fibrillation and myocardial stunning, the identification of biomarkers in ischaemic heart disease and the acquisition of mechanistic insights into myocardial protection during ischaemia and reperfusion . In heart failure (HF), proteome analyses have revealed changes concerning proteins of the extracellular matrix, cardiomyocyte cytoskeleton, contractile apparatus, energy production and cardiomyocyte protection that are up‐ or down‐regulated ( Table ) …”