Examining Cardiomyocyte Dysfunction Using Acute Chemical Induction of an Ageing Phenotype

Abstract

Much effort is focussed on understanding the structural and functional changes in the heart that underlie age-dependent deterioration of cardiac performance. Longitudinal studies, using aged animals, have pinpointed changes occurring to the contractile myocytes within the heart. However, whilst longitudinal studies are important, other experimental approaches are being advanced that can recapitulate the phenotypic changes seen during ageing. This study investigated the induction of an ageing cardiomyocyte phenotypic change by incubation of cells with hydroxyurea for several days ex vivo. Hydroxyurea incubation has been demonstrated to phenocopy age- and senescence-induced changes in neurons, but its utility for ageing studies with cardiac cells has not been examined. Incubation of neonatal rat ventricular myocytes with hydroxyurea for up to 7 days replicated specific aspects of cardiac ageing including reduced systolic calcium responses, increased alternans and a lesser ability of the cells to follow electrical pacing. Additional functional and structural changes were observed within the myocytes that pointed to ageing-like remodelling, including lipofuscin granule accumulation, reduced mitochondrial membrane potential, increased production of reactive oxygen species, and altered ultrastructure, such as mitochondria with disrupted cristae and disorganised myofibres. These data highlight the utility of alternative approaches for exploring cellular ageing whilst avoiding the costs and co-morbid factors that can affect longitudinal studies.

Endothelial cells from umbilical cord of women affected by gestational diabetes: A suitable in vitro model to study mechanisms of early vascular senescence in diabetes

“…In parallel with the impairment of ΔΨm, MTT test demonstrates that GD‐cells exhibited a slight but significant reduced viability compared to control cells 65 . Additionally, all ultrastructural alterations in intracellular organelles shown in Figure 4 are indicative of compromised cell integrity that may be involved in onset and maintaining of endothelial senescence 74 …”

“…65 Additionally, all ultrastructural alterations in intracellular organelles shown in Figure 4 are indicative of compromised cell integrity that may be involved in onset and maintaining of endothelial senescence. 74 It is accepted that mitochondrial dysfunction is quite often associated with chronic hyperglycemia and the changes in mitochondria leading to the generation of ROS are a part of the mechanism that triggers cell senescence by inducing both DNA damage and by translational and post-translational modifications of other macromolecules. The increase in ROS if not properly buffered by cell systems can lead to permanent modification of cell senescence phenotype.…”