Negative-feedback regulation of ATP release: ATP release from cardiomyocytes is strictly regulated during ischemia

Abstract

Extracellular ATP acts as a potent agonist on cardiomyocytes, inducing a broad range of physiological responses via P2 purinoceptors. Its concentration in the interstitial space within the heart is elevated during ischemia or hypoxia due to its release from a number of cell types, including cardiomyocytes. However, the exact mechanism responsible for the release of ATP from cardiomyocytes during ischemia is not known. In this study, we investigated whether and how the release of ATP was strictly regulated during ischemia in cultured neonatal rat cardiomyocytes. Ischemia was mimicked by oxygen-glucose deprivation (OGD). Exposure of cardiomyocytes to OGD resulted in an increase in the concentration of extracellular ATP shortly after the onset of OGD (15 min), and the increase was reversed by treatment with blockers of maxi-anion channels.Unexpectedly, at 1 and 2 hours after the onset of OGD, the blocking of maxi-anion channels increased the concentration of extracellular ATP, and the increase was significantly suppressed by co-treatment with blockers of hemichannels, suggesting that ATP release via maxi-anion channels was involved in the suppression of ATP release via hemichannels during persistent OGD. Here we show the possibility that the release of 3 ATP from cardiomyocytes was strictly regulated during ischemia by negative-feedback mechanisms; that is, maxi-anion channel-derived ATP-induced suppression of ATP release via hemichannels in cardiomyocytes.4

mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy

“…TSC2 ablation in the heart led to not only cardiac dysfunction, but also a decrease in heart rate. ATP is released from cardiomyocytes [ 39 , 40 ] and immediately metabolized to adenosine by ATPases that have their catalytic domain on the outer side of plasma membrane. Since adenosine is known to have a negative effect on heart rate [ 41 ], increased cytosolic ATP level may result in a decrease in heart rate in TSC2 -/- mice.…”

Purinergic Signaling and Blood Vessels in Health and Disease

“…Others have shown that ischemia is accompanied by an increased release of ATP from cardiac myocytes and sympathetic nerves (Lai and Nishi, 2000;Sesti et al, 2003;Clarke et al, 2009). It has been suggested that release of ATP from cardiomyocytes is strictly regulated during ischemia by a negative feedback mechanism consisting of maxi-anion channel-derived ATP-induced suppression of ATP release via hemichannels in cardiomyocytes (Kunugi et al, 2011). In a recent article (Cosentino et al, 2012), it was shown that ischemic/ hypoxic stress induced rapid ATP release from cultured cardiomyocytes and that distinct P2 receptors regulated cardiomyocyte death, perhaps via P2X 7 and P2Y 2 receptors.…”

Cardiac purinergic signalling in health and disease

“…It has been suggested that release of ATP from cardiomyocytes is strictly regulated during ischaemia by a negative feedback mechanism consisting of maxi-anion channel-derived ATP-induced suppression of ATP release via hemichannels in cardiomyocytes [586]. In a more recent study, it was shown that ischaemic/hypoxic stress induced rapid ATP release from cultured cardiomyocytes and that distinct P2R, perhaps P2X7R and P2Y2R, regulated cardiomyocyte death [587].…”