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Off-Target Effects of P2Y12 Receptor Inhibitors: Focus on Early Myocardial Fibrosis Modulation
Francesca Lofrumento1, Natasha Irrera1, Roberto Licordari1
1Department of Clinical and Experimental Medicine, Policlinic "G. Martino", University of Messina, 98122 Messina, Italy.
Abstract:
Several studies have demonstrated that, beyond their antithrombotic effects, P2Y12 receptor inhibitors may provide additional off-target effects through different mechanisms. These effects range from the preservation of endothelial barrier function to the modulation of inflammation or stabilization of atherosclerotic plaques, with an impact on different cell types, including endothelial and immune cells. Many P2Y12 inhibitors have been developed, from ticlopidine, the first thienopyridine, to the more potent non-thienopyridine derivatives such as ticagrelor which may promote cardioprotective effects following myocardial infarction (MI) by inhibiting adenosine reuptake through sodium-independent equilibrative nucleoside transporter 1 (ENT1). Adenosine may affect different molecular pathways involved in cardiac fibrosis, such as the Wnt (wingless-type)/beta (β)-catenin signaling. An early pro-fibrotic response of the epicardium and activation of cardiac fibroblasts with the involvement of Wnt1 (wingless-type family member 1)/β-catenin, are critically required for preserving cardiac function after acute ischemic cardiac injury. This review discusses molecular signaling pathways involved in cardiac fibrosis post MI, focusing on the Wnt/β-catenin pathway, and the off-target effect of P2Y12 receptor inhibition. A potential role of ticagrelor was speculated in the early modulation of cardiac fibrosis, thanks to its off-target effect.
Insights
P2Y12 inhibitors like ticagrelor may offer cardioprotection post myocardial infarction (MI) through off-target effects. Ticagrelor may modulate cardiac fibrosis via the Wnt/β-catenin pathway, preserving heart function after injury.
Area of Science:
- Cardiovascular Pharmacology
- Molecular Cardiology
- Translational Medicine
Background:
- P2Y12 receptor inhibitors possess antithrombotic and potential off-target effects.
- These off-target effects include endothelial barrier preservation, inflammation modulation, and plaque stabilization.
- Ticagrelor, a potent non-thienopyridine P2Y12 inhibitor, may offer cardioprotective benefits post myocardial infarction (MI).
Purpose of the Study:
- To review molecular signaling pathways in cardiac fibrosis following MI.
- To explore the off-target effects of P2Y12 receptor inhibition.
- To investigate the potential role of ticagrelor in modulating cardiac fibrosis post-MI.
Main Methods:
- Literature review of studies on P2Y12 inhibitors, myocardial infarction, cardiac fibrosis, and Wnt/β-catenin signaling.
- Analysis of proposed mechanisms for ticagrelor's off-target effects.
- Discussion of adenosine's role in cardiac fibrosis and its interaction with Wnt/β-catenin signaling.
Main Results:
- P2Y12 inhibitors exhibit diverse off-target effects impacting endothelial and immune cells.
- Ticagrelor may inhibit adenosine reuptake via ENT1, influencing cardiac pathways.
- Adenosine and the Wnt/β-catenin pathway are implicated in early pro-fibrotic responses crucial for cardiac repair post-MI.
Conclusions:
- P2Y12 receptor inhibition, particularly by ticagrelor, presents potential therapeutic strategies beyond antithrombosis.
- Ticagrelor's off-target inhibition of adenosine reuptake may modulate the Wnt/β-catenin pathway.
- Ticagrelor shows potential for early modulation of cardiac fibrosis, contributing to cardioprotection after MI.
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