Korean Circ J.  2022 Oct;52(10):737-754. 10.4070/kcj.2022.0162.

Pharmacological Approaches to Limit Ischemic and Reperfusion Injuries of the Heart: Analysis of Experimental and Clinical Data on P2Y ₁₂ Receptor Antagonists

• Maslov LN
• Popov SV
• Mukhomedzyanov AV
• Derkachev IA
• Ryabov VV
• Boshchenko AA
• Prasad NR
• Sufianova GZ
• Khlestkina MS
• Gareev I

• KMID: 2534038
• DOI: http://doi.org/10.4070/kcj.2022.0162

Abstract

Ischemic and reperfusion injuries of the heart underlie the pathogenesis of acute myocardial infarction (AMI) and sudden cardiac death. The mortality rate is still high and is 5–7% in patients with ST-segment elevation myocardial infarction. The review is devoted to pharmacological approaches to limitation of ischemic and reperfusion injuries of the heart. The article analyzes experimental evidence and the clinical data on the effects of P2Y ₁₂ receptor antagonists on the heart’s tolerance to ischemia/reperfusion in animals with coronary artery occlusion and reperfusion and also in patients with AMI. Chronic administration of ticagrelor prevented adverse remodeling of the heart. There is evidence that sphingosine-1-phosphate is the molecule that mediates the infarct-reducing effect of P2Y ₁₂ receptor antagonists. It was discussed a role of adenosine in the cardioprotective effect of ticagrelor.

Keyword

Heart; Ischemia; Reperfusion; Purinergic P2Y ₁₂ receptor antagonists; Cardiac remodeling

Figure

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  Figure 1 Effects of platelet activation during ischemia/reperfusion.The pathogenic effect of platelets on the reperfused heart depends on their activation, which causes the expression of P-selectin and LDH release.LDH = lactate dehydrogenase.

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  Figure 2 P2Y12 receptor inhibitors. (A) Chemical structure of P2Y12 receptor antagonists (B) Chemical structure of S1P.S1P = sphingosine-1-phosphate.

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  Figure 3 The hypothetical mechanism of the cardioprotective effect of P2Y12 receptor inhibitors.Inhibition of P2Y12 receptors results in the release of cardioprotective substance S1P from activated platelets. S1P increases PKC activity in myocardial tissue and can activate ERKs, PI3K, AMPK and PKC. S1P reduces infarct size in ischemia/reperfusion by activating Akt and STAT-3. S1P may prevent reperfusion injury of the heart through activation of Akt and inhibition of GSK-3β phosphorylation.Inhibitors of P2Y12 receptors induce an increase in the level of adenosine in myocardial tissue. There is evidence that they can activate the A3 adenosine receptor. However, there is no evidence that endogenous adenosine or adenosine receptors are involved in reducing the infarction of inhibitors of P2Y12 receptors in vivo.Akt = Akt kinase; AMPK = AMP-activated protein kinase; ERK = extracellular signal-regulated kinases; GSK-3β = glycogen synthase kinase-3β; PI3K = phosphatidylinositol (4,5)-bisphosphate 3-kinase; PKC = protein kinase C; S1P = sphingosine-1-phosphate; STAT-3 = signal transducer and activator of transcription 3.

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