Radixin Relocalization and Nonmuscle α-Actinin Expression Are Features of Remodeling Cardiomyocytes in Adult Patients with Dilated Cardiomyopathy

Abstract

Background. Pediatric patients show an impressive capacity of cardiac regeneration. In contrast, severely deteriorated adult hearts do usually not recover. Since cardiac remodeling—involving the expression of fetal genes—is regarded as an adaptation to stress, we compared hearts of adult patients suffering from dilated cardiomyopathy (DCM) with remodeling of cultured neonatal (NRC) as well as adult (ARC) rat cardiomyocytes and the developing postnatal myocardium. Methods. NRC and ARC were stimulated with serum and cardiac morphogens derived from DCM hearts. Protein synthesis (PS) as well as protein accumulation (PA) was measured, and cell survival was determined under ischemic conditions. Fetal markers were investigated by Western blot. Biomarkers of remodeling were analyzed in controls, DCM, and 2- to 6-month-old children with tetralogy of Fallot as well as in neonatal and adult rats by immunofluorescence. Results. In NRC, serum and morphogens strongly stimulated PS and PA and the reestablishment of cell-cell contacts (CCC). In ARC, both stimulants increased PS and CCC, but PA was only elevated after serum stimulation. In contrast to serum, morphogen treatment resulted in the expression of fetal genes in ARC as determined by nonmuscle α-actinin-1 and α-actinin-4 expression (NM-actinins) and was associated with increased survival under ischemia. NM-actinins were present in cardiomyocytes of DCM in a cross-striated pattern reminiscent of sarcomeres as well as in extensions of the area of the intercalated disc (ID). NM-actinins are expressed in NRC and in the developing heart. Radixin staining revealed remodeling of the area of the ID in DCM almost identical to stimulated cultured ARC. Conclusions. Remodeling was similar in ARC and in cardiomyocytes of DCM suggesting evolutionary conserved mechanisms of regeneration. Despite activation of fetal genes, the atrophy of ARC indicates differences in their regenerative capacity from NRC. Cardiac-derived factors induced NM-actinin expression and increased survival of ischemic ARC while circulating molecules were less effective. Identification of these cardiac-derived factors and determination of their individual capacity to heal or damage are of particular importance for a biomarker-guided therapy in adult patients.

Myocardial Accumulations of Reg3A, Reg3γ and Oncostatin M Are Associated with the Formation of Granulomata in Patients with Cardiac Sarcoidosis

“…Threonine residue 308 (Thr308) in the Akt kinase was strongly phosphorylated, although little activation of serine 473 was observed. ERM proteins (ezrin, radixin and moesin) are a further indicator of cellular activation [ 10 , 11 ]. They stabilize the membrane and the actin cytoskeleton and are regarded as linker proteins.…”

The MEK/ERK Module Is Reprogrammed in Remodeling Adult Cardiomyocytes

“…Morphogens also induced the reexpression of α-actinin-1 and β-actin, but both proteins were barely detectable in serum-treated groups ( Figure 1 A,B). α-Actinin-1 appears to be a new marker of cardiac remodeling since it is reexpressed in cardiomyocytes of patients with dilated cardiomyopathy, aortic stenosis, and myocardial infarction, as well as in mice with myocarditis, dilated cardiomyopathy, and infarction [ 11 , 12 , 13 , 16 , 25 , 26 , 27 ]. Skeletal actin is present in adult rat cardiomyocytes and was downregulated by serum at day 10 but recovered thereafter.…”

“…Primary cultures of adult cardiomyocytes offer an ideal toolbox to analyze the general behavior of stress-activated myocytes in the diseased myocardium since they transfer their genetic, epigenetic, and proteomic statuses into the culture dish [ 25 , 27 ]. By this a number of novel biomarkers of cardiac remodeling and failure can be determined and basic principles of cardiac disease development analyzed [ 24 , 25 , 27 ]. Here, we wanted to know whether structural and MAPK remodeling can be observed in cardiomyocytes of patients with dilated cardiomyopathy (DCM).…”

Identification of key pathways and genes in polycystic ovary syndrome via integrated bioinformatics analysis and prediction of small therapeutic molecules

“…The GO and pathway enrichment analysis was of great importance for interpreting the molecular mechanisms of the key cellular activities in PCOS. RPS5 [ 37 ], RBM3 [ 38 ], BAK1 [ 39 ], NDUFC2 [ 40 ], NDUFS4 [ 41 ], NDUFS5 [ 42 ], UQCRFS1 [ 43 ], COX6B1 [ 44 ], NDUFA13 [ 45 ], PRMT1 [ 46 ], RDX (radixin) [ 47 ], EPHB4 [ 48 ], SYNE2 [ 49 ], DNAH5 [ 50 ], NEDD4L [ 51 ], PDE4B [ 52 ] and CTNND1 [ 53 ] plays a critical role in the process of cardiovascular disease, but these genes might be linked with development of PCOS. Ostergaard et al [ 54 ], Zi et al [ 55 ], Kunej et al [ 56 ], Van der Schueren et al [ 57 ], Jin et al [ 58 ], Emdad et al [ 59 ], Liu et al [ 60 ], Scherag et al [ 61 ], Shi and Long [ 62 ], Sharma et al [ 63 ], Parente et al [ 64 ], Saint-Laurent et al [ 65 ] and Lee [ 66 ] demonstrated that over expression of COA3, PHB (prohibitin), UQCRC1, COX4I1, IFI27, MTDH (metadherin), S100A16, SDCCAG8, GLI2, NTN1, NLGN2, FGFR3 and PTPRN2 could cause obesity, but these genes might be involved in progression of PCOS.…”