ADORA2b Signaling in Cardioprotection

Abstract

Cardiovascular disease is the number one cause of death worldwide. A powerful strategy for cardioprotection would be to identify specific molecules or targets that mimic ischemic preconditioning (IP), where short non-lethal episodes of ischemia and reperfusion prior to myocardial infarction result in dramatic reduction of infarct sizes. Since 1960 researchers believed that adenosine has a strong cardio-protective potential. In fact, with the discovery of cardiac IP in 1986 by Murry et al., adenosine was the first identified molecule that was used in studying the underlying mechanism of IP. Today we know, based on genetic studies, that adenosine is crucial for IP mediated cardio-protection and that the adenosine receptors ADORA1, ADORA2a and ADORA2b play an important role. However, the ADORA2b receptor is the only receptor so far which has been found to play a role in human and murine myocardial ischemia. With recent advances using tissue specific mice for the ADORA2b, we were able to uncover cardiomyocytes and endothelia as the responsible cell type for cardiac IP. Using a wide search for ADORA2b downstream targets, our group identified the circadian rhythm protein, Period 2 (PER2), as a novel target for IP mediated cardioprotection. Mechanistic studies on PER2 mediated cardioprotection revealed an important role for PER2 in optimizing cardiac metabolism through activation of oxygen saving pathways. Thus, cardiomyocyte or endothelial expressed ADORA2b or the downstream circadian rhythm protein PER2 are key targets for cardiac IP and could represent novel strategies to treat or prevent MI.

Keywords: Adora2b; CD73; Cardiac Period 2; Cardiomyocytes; Ischemia-reperfusion Injury; Ischemic Preconditioning; Myocardial Infarction.

Figure 1. Role of ADORA2b activation in IR-injury and IP mediated cardioprotection

CD73 generates extracellular adenosine via phosphohydrolysis of AMP. Adenosine can then bind to the ADORA2b and activate it. During ischemia and reperfusion (IR) injury, activation of the ADORA2b on polymorph nuclear leukocytes (PMNs) attenuates myocardial infarct sizes by reducing TNF levels (A). During ischemic preconditioning (IP) of the heart, activation of the ADORA2b on cardiomyocytes or endothelial cells confers cardioprotection (B). IP-cardioprotection is mediated through a downstream protein known as Period 2 (PER2) via cAMP. PER2 stabilization allows the oxygen deprived myocardium to switch its metabolism to a more oxygen-efficient metabolism thereby decreasing infarct sizes during ischemia (C). Alternative cardiac PER2 stabilization can be achieved by exposure of mice to intense light which also leads to reduced infarct sizes in a murine model for myocardial ischemia (D).