Possible Molecular Mechanisms Underlying Age-Related Cardiomyocyte Apoptosis in the F344XBN Rat Heart

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.

Variations in the protein level of Omi/HtrA2 in the heart of aged rats may contribute to the increased susceptibility of cardiomyocytes to ischemia/reperfusion injury and cell death

“…Accumulating evidence indicates that myocardial apoptosis, a gene-regulated programmed cell death, markedly increases with aging (Kajstura et al 1996;Kakarla et al 2010;Boyle et al 2011). Recently, data demonstrated the enhanced rates of apoptosis in the aging heart exacerbated myocardial ischemia/ reperfusion (MI/R) injury in not only animals but also humans .…”

Efficacy of Female Rat Models in Translational Cardiovascular Aging Research

“…The age-associated increase in apoptosis appears to be due not only to the activation of proapoptotic molecules but also to decreases in antiapoptotic NF- κ B, Bcl-xL, and Grx1 signaling [ 130 ]. Another work has demonstrated that the aging male F344xBN rat heart is characterized by increases in TdT-mediated dUTP nick end labeling- (TUNEL-) positive nuclei, caspase-3 activation, caspase-dependent cleavage of alpha-fodrin, and diminished phosphorylation of protein kinase B/Akt (Thr308) [ 133 ]. The increase of apoptosis in the aging male F344xBN was highly correlated to age-associated increases in oxidative-nitrosative stress.…”

Expresión disminuida de caspasa 3 asociada al polimorfismo del gen del antígeno-4 asociado a linfocito T-citotóxico (CTLA4) en pacientes chilenos con diabetes tipo 1

“…Sin embargo, esta diferencia de edad podría estar afectando la actividad de caspasa 3. En otros modelos celulares (cardiomiocitos en cultivo, células progenitoras endoteliales y músculo) se ha observado que la concentración de caspasa 3 está aumentada y que su actividad tiende a ser mayor con la edad [37][38][39] . Este antecedente es relevante y a pesar de que no hay antecedentes en CMPs y que los controles también son jóvenes, debiera interpretarse con cautela.…”