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- Mahdi, A., et al.
(författare)
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The red blood cell as a mediator of endothelial dysfunction in patients with familial hypercholesterolemia and dyslipidemia
- 2023
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 293:2, s. 228-245
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Tidskriftsartikel (refereegranskat)abstract
- Background Patients with familial hypercholesterolemia (FH) display high levels of low-density lipoprotein cholesterol (LDL-c), endothelial dysfunction, and increased risk of premature atherosclerosis. We have previously shown that red blood cells (RBCs) from patients with type 2 diabetes induce endothelial dysfunction through increased arginase 1 and reactive oxygen species (ROS). Objective To test the hypothesis that RBCs from patients with FH (FH-RBCs) and elevated LDL-c induce endothelial dysfunction. Methods and results FH-RBCs and LDL-c >5.0 mM induced endothelial dysfunction following 18-h incubation with isolated aortic rings from healthy rats compared to FH-RBCs and LDL-c <2.5 mM or RBCs from healthy subjects (H-RBCs). Inhibition of vascular but not RBC arginase attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. Furthermore, arginase 1 but not arginase 2 was elevated in the vasculature of aortic segments after incubation with FH-RBCs and LDL-c >5.0 mM. A superoxide scavenger, present throughout the 18-h incubation, attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. ROS production was elevated in these RBCs in comparison with H-RBCs. Scavenging of vascular ROS through various antioxidants also attenuated the degree of endothelial dysfunction induced by FH-RBCs and LDL-c >5.0 mM. This was corroborated by an increase in the lipid peroxidation product 4-hydroxynonenal. Lipidomic analysis of RBC lysates did not reveal any significant changes across the groups. Conclusion FH-RBCs induce endothelial dysfunction dependent on LDL-c levels via arginase 1 and ROS-dependent mechanisms.
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- Jiao, T, et al.
(författare)
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Erythrocytes from patients with ST-elevation myocardial infarction induce cardioprotection through the purinergic P2Y13 receptor and nitric oxide signaling
- 2022
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Ingår i: Basic research in cardiology. - : Springer Science and Business Media LLC. - 1435-1803 .- 0300-8428. ; 117:1, s. 46-
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Tidskriftsartikel (refereegranskat)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 P2Y13 receptor was expressed in RBCs and the cardioprotection was abolished by the P2Y13 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 P2Y13 receptor and the NO–sGC–PKG pathway.
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- Mahdi, A, et al.
(författare)
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Erythrocytes Induce Endothelial Injury in Type 2 Diabetes Through Alteration of Vascular Purinergic Signaling
- 2020
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Ingår i: Frontiers in pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11, s. 603226-
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Tidskriftsartikel (refereegranskat)abstract
- It is well established that altered purinergic signaling contributes to vascular dysfunction in type 2 diabetes (T2D). Red blood cells (RBCs) serve as an important pool for circulating ATP and the release of ATP from RBCs in response to physiological stimuli is impaired in T2D. We recently demonstrated that RBCs from patients with T2D (T2D RBC) serve as key mediators of endothelial dysfunction. However, it remains unknown whether altered vascular purinergic signaling is involved in the endothelial dysfunction induced by dysfunctional RBCs in T2D. Here, we evaluated acetylcholine-induced endothelium-dependent relaxation (EDR) of isolated rat aortas after 18 h ex vivo co-incubation with human RBCs, and aortas of healthy recipient rats 4 h after in vivo transfusion with RBCs from T2D Goto-Kakizaki (GK) rats. Purinergic receptor (PR) antagonists were applied in isolated aortas to study the involvement of PRs. EDR was impaired in aortas incubated with T2D RBC but not with RBCs from healthy subjects ex vivo, and in aortas of healthy rats after transfusion with GK RBCs in vivo. The impairment in EDR by T2D RBC was attenuated by non-selective P1R and P2R antagonism, and specific A1R, P2X7R but not P2Y6R antagonism. Transfusion with GK RBCs in vivo impaired EDR in aortas of recipient rats, an effect that was attenuated by A1R, P2X7R but not P2Y6R antagonism. In conclusion, RBCs induce endothelial dysfunction in T2D via vascular A1R and P2X7R but not P2Y6R. Targeting vascular purinergic singling may serve as a potential therapy to prevent endothelial dysfunction induced by RBCs in T2D.
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- Mahdi, A, et al.
(författare)
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Red Blood Cell Peroxynitrite Causes Endothelial Dysfunction in Type 2 Diabetes Mellitus via Arginase
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:7
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Tidskriftsartikel (refereegranskat)abstract
- We recently showed that red blood cells (RBCs) from patients with type 2 diabetes mellitus (T2DM-RBCs) induce endothelial dysfunction through a mechanism involving arginase I and reactive oxygen species. Peroxynitrite is known to activate arginase in endothelial cells. Whether peroxynitrite regulates arginase activity in RBCs, and whether it is involved in the cross-talk between RBCs and the vasculature in T2DM, is unclear and elusive. The present study was designed to test the hypothesis that endothelial dysfunction induced by T2DM-RBCs is driven by peroxynitrite and upregulation of arginase. RBCs were isolated from patients with T2DM and healthy age matched controls. RBCs were co-incubated with aortae isolated from wild type rats for 18 h in the absence and presence of peroxynitrite scavenger FeTTPS. Evaluation of endothelial function in organ chambers by cumulative addition of acetylcholine as well as measurement of RBC and vessel arginase activity was performed. In another set of experiments, RBCs isolated from healthy subjects (Healthy RBCs) were incubated with the peroxynitrite donor SIN-1 with subsequent evaluation of endothelial function and arginase activity. T2DM-RBCs, but not Healthy RBCs, induced impairment in endothelial function, which was fully reversed by scavenging of RBC but not vascular peroxynitrite with FeTPPS. Arginase activity was up-regulated by the peroxynitrite donor SIN-1 in Healthy RBCs, an effect that was inhibited by FeTTPS. Healthy RBCs co-incubated with aortae in the presence of SIN-1 caused impairment of endothelial function, which was inhibited by FeTTPS or the arginase inhibitor ABH. T2DM-RBCs induced up-regulation of vascular arginase, an effect that was fully inhibited by FeTTPS. Collectively, our data indicate that RBCs impair endothelial function in T2DM via an effect that is driven by a peroxynitrite-mediated increase in arginase activity. This mechanism may be targeted in patients with T2DM for improvement in endothelial function.
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