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Differential regulation of cardiomyocyte death/survival signalling in human dilated cardiomyopathy
Author(s) -
Dzimiri Nduna,
Muiya Paul,
Andres Editha,
Afrane Barima
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a233-c
Subject(s) - dilated cardiomyopathy , medicine , apoptosis , programmed cell death , receptor , cardiomyopathy , cardiology , endocrinology , protein kinase b , homeostasis , signal transduction , heart failure , biology , microbiology and biotechnology , biochemistry
We tested the possibility that the heart harbors multiple death‐related signaling proteins that may play different roles in balancing between pro‐ and anti‐apoptotic signaling in human dilated cardiomyopathy (DCM). Compared to healthy donor hearts, while mRNA (n=8) and protein expression (n=5) of all studied death receptors (DR1‐6) were markedly elevated only on the left heart side, DR4 and 5 were also increased on the right side. In contrast, decoy receptor 1 (DcR1) was slightly, and DcR3 significantly decreased (p<0.0001) in all chambers. These changes were associated with global myocardial DNA fragmentation, marked elevation in PARP activity in left atria (LA) (1.7‐fold; p<0.05) and in right atria (1.1‐fold; p<0.05) and in Bcl‐2/Bax ratio (p<0.005) in all chambers against reduced PI3K/Akt activity. Interestingly, Erk activity was elevated in the left heart side by 95.3% (p<0.05) in left ventricles (LV) and 130.2% (p<0.05) in LA, accompanied by 45.2% increase (p<0.05) in p38 MAPK activity in LV. SAPK/JNK activity was increased by 45.1% (p<0.05) in LV and 77.8% (p<0.05) in LA. Our results show differential activation of signalling entities regulating partly counteractive mechanisms associated with cell death, survival and homeostasis in DCM. The selectivity in cardiac DR expression points to their serving various purposes in balancing between cell death and survival in heart muscle disease. The study also suggests that changes associated with left ventricular overload may underlie receptor mediated mode of cell death that occurs in cardiomyopathy, contributory to dilatation and failure.