Adenosine impacts heart function and survival under normal and pathological conditions by interacting at the cell surface with adenosine receptor subtypes A1, A2 and A3, and modulating glucose transport, glycolysis, glucose oxidation, neurotransmitter release and contractility. Adenosine is also a negative feedback regulator of 2-adrenergic stimulation, thereby protecting the heart from the lethal consequences of adrenergic overdrive. By modulating protein kinase C (PKC?) and phosphatase activities, adenosine modulates processes that require substrate phosphorylation for activation, such as preconditioning and apoptosis. As a substrate for adenosine kinase, adenosine is also vital precursor of the cardiomyocyte nucleotide pool. The resulting AMP modulates the activity of AMP Kinase, a vital regulator of the cellular metabolic state, prior to further phosphorylation to ADP and ATP. Adenosine enters and leaves the cell via specific concentrative and equilibrative transporters. In that the transport of adenosine across the cellular membrane is a focal point around which revolve many scenarios that critically impact the function of the heart, disruption of adenosine transport can be detrimental to heart survival. In the aged heart, evidence has been found suggesting animal impairment of adenosine transport. It is hypothesized that in the aged ventricular myocardium, the adenosine concentrative and equilibrative transporter activities are reduced. The goal of this study is to verify this hypothesis enabling further study of mechanisms by which aging alters adenosine transport mechanisms. This hypothesis will be studied by considering the following SPECIFIC AIMS:
Specific Aim 1 : Determine if the appearance of intracellular free adenosine in the aged heart rises to a greater level than in the young adult heart when cellular adenosine production is enhanced.
Specific Aim 2 : Determine if the protein and mRNA levels of adenosine transporters are depressed in the aged heart.
Specific Aim 3 : Determine if the adenosine transporters are phosphorylated by PKC in the adenosine- or phorbol-stimulated heart and if the level of phosphorylation attained is depressed in the aged vs young adult heart. These studies will further the development of additional hypotheses designed to gain a better understanding of how aging alters heart function.
Adenosine is a naturally produced metabolite that is important to the normal metabolic, contractile and electrical function of the heart. Adenosine transporters located in cardiomyocyte membranes control the movement of adenosine into and out of the cell, thus influencing the many aspects of cellular function modulated by adenosine. In the aged heart transporter function appears to be attenuated. This study proposes experiments exploring the basis for the impaired transporter function.
| Fenton, Richard A; Dobson Jr, James G (2012) Reduced adenosine release from the aged mammalian heart. J Cell Physiol 227:3709-14 |
