Erythrocytes Induce Endothelial Injury in Type 2 Diabetes Through Alteration of Vascular Purinergic Signaling.

Ali Mahdi,Lara Garib,Zhichao Zhou,Michael Alvarsson,John Tengbom,John Pernow,Jiangning Yang,Tong Jiao,Yahor Tratsiakovich

doi:10.3389/fphar.2020.603226

Ali Mahdi, Lara Garib + Show 7 more

Open Access

https://doi.org/10.3389/fphar.2020.603226

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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.

Highlights

Type 2 diabetes (T2D) is an important risk factor for the development of cardiovascular disease including ischemic heart disease and myocardial infarction (Paneni et al, 2013)
The U46619- and KCl-induced contraction in aortas incubated with type 2 diabetes (T2D) Red blood cells (RBCs) were comparable with that in aortas incubated with H RBC (Supplementary Figure S1)
In accordance with our recent findings using the well-established ex vivo human RBC-vessel co-incubation model (Zhou et al, 2018; Mahdi et al, 2019; Mahdi et al, 2020), T2D RBC but not H RBC or buffer induced vascular endothelial dysfunction, which is evident from the significant impairment in endotheliumdependent relaxation (EDR) in rat aortas incubated with T2D RBC (Figure 1A)

Summary

Introduction

Type 2 diabetes (T2D) is an important risk factor for the development of cardiovascular disease including ischemic heart disease and myocardial infarction (Paneni et al, 2013). Both microvascular and macrovasular complications significantly contribute to the increase in mortality and morbidity in the large population with T2D (Paneni et al, 2013). Endothelial dysfunction plays a pivotal role in the etiology of T2D-induced vascular complications This is characterized by an imbalance between endothelium-derived vasodilators such as nitric oxide (NO) and adenosine triphosphate (ATP), and vasoconstrictors such as reactive oxygen species (ROS) and ATP including its down-stream purinergic signaling (Gimbrone and Garcia-Cardena, 2016; Mahdi et al, 2018). There is a clinical need for improved understanding of these disease mechanisms in order to develop new therapeutic strategies for the treatment of vascular complications

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