Erythrocytes from patients with ST-elevation myocardial infarction induce cardioprotection through the purinergic P2Y13 receptor and nitric oxide signaling

Abstract

Red blood cells (RBCs) are suggested to play a role in cardiovascular regulation by exporting nitric oxide (NO) bioactivity and ATP under hypoxia. It remains unknown whether such beneficial effects of RBCs are protective in patients with acute myocardial infarction. We investigated whether RBCs from patients with ST-elevation myocardial infarction (STEMI) protect against myocardial ischemia–reperfusion injury and whether such effect involves NO and purinergic signaling in the RBCs. RBCs from patients with STEMI undergoing primary coronary intervention and healthy controls were administered to isolated rat hearts subjected to global ischemia and reperfusion. Compared to RBCs from healthy controls, RBCs from STEMI patients reduced myocardial infarct size (30 ± 12% RBC healthy vs. 11 ± 5% RBC STEMI patients, P < 0.001), improved recovery of left-ventricular developed pressure and dP/dt and reduced left-ventricular end-diastolic pressure in hearts subjected to ischemia–reperfusion. Inhibition of RBC NO synthase with L-NAME or soluble guanylyl cyclase (sGC) with ODQ, and inhibition of cardiac protein kinase G (PKG) abolished the cardioprotective effect. Furthermore, the non-selective purinergic P2 receptor antagonist PPADS but not the P1 receptor antagonist 8PT attenuated the cardioprotection induced by RBCs from STEMI patients. The P2Y 13 receptor was expressed in RBCs and the cardioprotection was abolished by the P2Y 13 receptor antagonist MRS2211. By contrast, perfusion with PPADS, L-NAME, or ODQ prior to RBCs administration failed to block the cardioprotection induced by RBCs from STEMI patients. Administration of RBCs from healthy subjects following pre-incubation with an ATP analog reduced infarct size from 20 ± 6 to 7 ± 2% ( P < 0.001), and this effect was abolished by ODQ and MRS2211. This study demonstrates a novel function of RBCs in STEMI patients providing protection against myocardial ischemia–reperfusion injury through the P2Y 13 receptor and the NO–sGC–PKG pathway. Supplementary Information The online version contains supplementary material available at 10.1007/s00395-022-00953-4.

Stimulation of Erythrocyte Soluble Guanylyl Cyclase Induces cGMP Export and Cardioprotection in Type 2 Diabetes

“… 8 , 9 Recent studies using mice with specific deletion of RBC eNOS demonstrated the importance of eNOS signaling in RBCs in blood pressure regulation 10 and myocardial ischemia-reperfusion (I/R). 11 Available data suggest that the cardioprotective factor released from RBCs in the setting of experimental myocardial I/R 4 as well as in patients with acute myocardial infarction 12 is derived from eNOS. However, the signaling downstream of eNOS remains unclear and controversial.…”

Erythrocyte-Derived microRNAs: Emerging Players in Cardiovascular and Metabolic Disease

“…1,2 In addition, RBCs have been shown to be physiological regulators of cardiovascular function, especially under hypoxic conditions. [2][3][4] In fact, a recent study demonstrated that RBCs are involved in the regulation of blood pressure. 5 Emerging evidence has revealed that RBCs undergo functional alteration in various cardiovascular and metabolic diseases.…”

Red Blood Cell-Mediated Cardioprotection Is Impaired in ST-Segment Elevation Myocardial Infarction Patients With Anemia

“…In experimental and clinical studies, it has been shown that RBC-derived endothelial nitric oxide synthase (eNOS) provides cardioprotection in acute myocardial infarction (AMI). 1 , 2 , 3 This cardioprotective role of RBCs appears to be mediated at least in part by activation of purinergic signaling via the P2Y 13 receptor and the NO–soluble guanylyl cyclase pathway within the RBCs and protein kinase G in the heart. 1 …”

“… 1 , 2 , 3 This cardioprotective role of RBCs appears to be mediated at least in part by activation of purinergic signaling via the P2Y 13 receptor and the NO–soluble guanylyl cyclase pathway within the RBCs and protein kinase G in the heart. 1 …”

“… 2 Experimental models and studies of anemia showed that remaining circulating RBCs become dysfunctional with signs of increased turnover, eryptosis, exaggerated membrane fragility, disturbed redox balance with increased production of reactive oxygen species, and uncoupled RBC-derived eNOS with reduced NO bioactivity. 1 , 2 , 3 …”