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Possible molecular mechanisms underlying age-related cardiomyocyte apoptosis in the F344XBN rat heart
Sunil K Kakarla1, Kevin M Rice, Anjaiah Katta
1Laboratory of Molecular Physiology, Robert C. Byrd Biotechnology Science Center, Department of Biological Sciences, 1700 3rd Avenue, Marshall University, Huntington, WV 25755-1090, USA.
Insights
Aging hearts show increased cardiomyocyte apoptosis, linked to changes in the cardiac dystrophin glycoprotein complex (DGC). These findings suggest DGC alterations contribute to age-related heart dysfunction and cell death.
Area of Science:
- Cardiovascular Biology
- Aging Research
- Cellular Biology
Background:
- Age-related cardiac dysfunction is a major cause of cardiovascular death.
- Cardiomyocyte apoptosis (programmed cell death) is implicated in pathological heart remodeling during aging.
Purpose of the Study:
- To investigate the effects of aging on cardiomyocyte apoptosis.
- To explore the association between aging, apoptosis, and the cardiac dystrophin glycoprotein complex (DGC).
Main Methods:
- Examined cardiomyocyte apoptosis in Fischer344 x Brown Norway F1 hybrid rats of different ages (6, 30, 36 months).
- Assessed markers of apoptosis including TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 activation.
- Analyzed protein kinase B/Akt phosphorylation and components of the cardiac dystrophin glycoprotein complex (DGC).
- Utilized immunohistochemical analysis to study DGC molecule localization.
Main Results:
- Aged hearts displayed increased TUNEL-positive nuclei and caspase-3 activation compared to younger hearts.
- Diminished phosphorylation of protein kinase B/Akt (Thr 308) was observed in aged hearts.
- Age-dependent increases in cardiomyocyte apoptosis correlated with altered DGC composition and elevated cytoplasmic IgG and albumin.
- Immunohistochemistry revealed qualitative differences in DGC molecule localization with aging.
Conclusions:
- Aging leads to increased cardiomyocyte apoptosis in the heart.
- Age-associated changes in the cardiac dystrophin glycoprotein complex (DGC) structure may contribute to increased cardiac apoptotic activity.
- These findings provide insights into the molecular mechanisms underlying age-related cardiac dysfunction.
Abstract:
Despite advances in treatment, age-related cardiac dysfunction still remains a leading cause of cardiovascular death. Recent data have suggested that increases in cardiomyocyte apoptosis may be involved in the pathological remodeling of heart. Here, we examine the effects of aging on cardiomyocyte apoptosis in 6-, 30-, and 36-month-old Fischer344 x Brown Norway F1 hybrid rats (F344XBN). Compared with 6-month hearts, aged hearts exhibited increased TdT-mediated dUTP nick end labeling-positive nuclei, caspase-3 activation, caspase-dependent cleavage of alpha-fodrin and diminished phosphorylation of protein kinase B/Akt (Thr 308). These age-dependent increases in cardiomyocyte apoptosis were associated with alterations in the composition of the cardiac dystrophin glycoprotein complex and elevated cytoplasmic IgG and albumin immunoreactivity. Immunohistochemical analysis confirmed these data and demonstrated qualitative differences in localization of dystrophin-glycoprotein complex (DGC) molecules with aging. Taken together, these data suggest that aging-related increases in cardiac apoptotic activity model may be due, at least in part, to age-associated changes in DGC structure.
