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ADORA2b Signaling in Cardioprotection
1University of Colorado School of Medicine Department of Anesthesiology, Aurora, CO 80045, USA.
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.
Insights
Cardioprotection strategies are crucial for treating heart disease. Researchers identified adenosine receptor 2B (ADORA2b) and Period 2 (PER2) as key targets for mimicking ischemic preconditioning, offering new ways to prevent heart attacks.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Ischemic Preconditioning
Background:
- Cardiovascular disease is a leading global cause of death.
- Ischemic preconditioning (IP) offers cardioprotection by mimicking short ischemia/reperfusion episodes.
- Adenosine and its receptors are implicated in IP-mediated cardioprotection.
Purpose of the Study:
- To identify novel molecular targets that mimic ischemic preconditioning (IP) for cardioprotection.
- To investigate the role of adenosine receptors, specifically ADORA2b, in cardiac IP.
- To explore downstream targets of ADORA2b involved in IP-mediated cardioprotection.
Main Methods:
- Utilized genetic studies and tissue-specific mice to investigate ADORA2b function in cardiac IP.
- Performed a comprehensive search for ADORA2b downstream targets.
- Conducted mechanistic studies on the identified target, Period 2 (PER2), in cardioprotection.
Main Results:
- Adenosine receptor 2B (ADORA2b) plays a crucial role in cardiac IP in both human and murine models.
- Cardiomyocytes and endothelial cells were identified as key cell types mediating cardiac IP via ADORA2b.
- The circadian rhythm protein Period 2 (PER2) was identified as a novel downstream target of ADORA2b, crucial for IP-mediated cardioprotection.
- PER2 optimizes cardiac metabolism by activating oxygen-saving pathways.
Conclusions:
- ADORA2b expressed in cardiomyocytes or endothelial cells is a key target for cardiac IP.
- The circadian rhythm protein PER2 is a novel mediator of IP-induced cardioprotection.
- Targeting ADORA2b or PER2 presents potential novel therapeutic strategies for preventing or treating myocardial infarction (MI).
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