Can we use chemical-induction of ageing to develop a model of cardiac ageing?

Masoud, Said; Bootman, Martin D.; McDonald, Fraser and Rietdorf, Katja (2016). Can we use chemical-induction of ageing to develop a model of cardiac ageing? In: 14th International Meeting of the European Calcium Society, 25-29 Sep 2016, Valladolid, Spain.

Abstract

Cardiovascular diseases are the leading cause of deaths worldwide, with age being one of the biggest risk factors. Cardiovascular ageing is characterised by a decline in cardiac function attributed to changes in ultrastructure and calcium homeostasis. Typically, celular ageing is studied longitudinally by comparing young and old animals. These studies are effective, but expensive and time consuming. Recent work has shown that neuronal ageing can be acutely studied by adding hydroxyurea (HU) or D-galactose to isolated cells, or giving it to animals. We want to test whether this chemically-induced ageing model can also be used to study ageing in cardiomyocytes. In this study, we induced ageing of neonatal rat ventricular myocytes (NRVM) by addition of 50 or 500 μM HU for 7 days. Using calcium imaging, we showed that HU treatment increased the frequency of spontaneous calcium transients after 2 Hz electrical field stimulation. Similarly, HU treatment decreased the ability of cardiomyocytes to follow electrical pacing and increased the generation of alternans; two known proarrhythmic behaviours. We also found an increase in the levels of autophagy, and a disruption of mitochondria after HU addition. EM analysis revealed that HU treatment increased the appearance of autophagosomes, rough sarcoplasmic reticulum and gangliosides. Our results indicate that prolonged incubation with HU evoked changes in the ultrastructure and calcium homeostasis of cardiomyocytes similar to those observed in naturally aged cells. We propose that chemically induced ageing provides a relevant model of cellular ageing, which can be applied acutely and inexpensively.

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