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Radixin Relocalization and Nonmuscle α-Actinin Expression Are Features of Remodeling Cardiomyocytes in Adult Patients
Ayse Cetinkaya1,2, Benedikt Berge1,2, Bedriye Sen-Hild3
1Department of Cardiac Surgery, Kerckhoff Heart Center, Benekestrasse 2-8, Bad Nauheim 61231, Germany.
Insights
Adult cardiomyocytes show limited regeneration compared to neonates, but cardiac-derived factors can induce fetal gene expression and improve survival in stressed adult heart cells, suggesting potential therapeutic targets.
Area of Science:
- Cardiovascular Biology
- Regenerative Medicine
- Cellular Cardiology
Background:
- Pediatric cardiomyocytes exhibit significant regenerative capacity, unlike adult hearts which typically do not recover from severe damage.
- Cardiac remodeling, characterized by fetal gene expression, is an adaptive response to stress.
- This study compares adult dilated cardiomyopathy (DCM) remodeling with neonatal and adult rat cardiomyocyte cultures and developing heart tissue.
Purpose of the Study:
- To investigate the mechanisms underlying cardiac regeneration and remodeling in adult versus neonatal cardiomyocytes.
- To compare the effects of cardiac morphogens and serum on cardiomyocyte protein synthesis, accumulation, and survival.
- To identify potential therapeutic targets for improving adult cardiac repair.
Main Methods:
- Neonatal (NRC) and adult (ARC) rat cardiomyocytes were stimulated with serum and DCM-derived morphogens.
- Protein synthesis, protein accumulation, and cell survival under ischemia were measured.
- Fetal gene markers (nonmuscle α-actinins) and intercalated disc remodeling (Radixin) were analyzed via Western blot and immunofluorescence.
Main Results:
- Neonatal cardiomyocytes showed robust responses to stimulation, including protein synthesis, accumulation, and cell-cell contact reestablishment.
- Adult cardiomyocytes responded to serum with increased protein synthesis and cell-cell contacts, and to morphogens with fetal gene expression (NM-actinins) and enhanced survival under ischemia.
- NM-actinins were observed in adult DCM cardiomyocytes in a sarcomeric pattern, and intercalated disc remodeling in DCM mirrored stimulated ARC.
Conclusions:
- Cardiac remodeling in adult DCM shares similarities with stimulated adult cardiomyocytes, suggesting conserved regenerative mechanisms.
- Despite fetal gene activation, adult cardiomyocytes exhibit atrophy, indicating differences in regenerative potential compared to neonatal cells.
- Cardiac-derived factors, not circulating molecules, induced NM-actinin expression and improved ischemic survival in adult cardiomyocytes, highlighting their therapeutic importance.
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.
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