Erythrocytes From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Via Arginase I

Zhou, Zhichao; Mahdi, Ali; Tratsiakovich, Yahor; Zahorán, Szabolcs; Kövamees, Oskar; Nordin, Filip; González, Arturo; Alvarsson, Michael; Östenson, Claes‐Göran; Andersson, Daniel; Hedin, Ulf; Hermesz, Edit; Lundberg, Jon O.; Yang, Jiangning; Pernow, John

doi:10.1016/j.jacc.2018.05.052

Cited by 141 publications

(181 citation statements)

References 19 publications

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“…Abnormal NO levels have been reported in vascular pathological conditions (Bondonno et al, 2016), and intervention in NO signaling can effectively prevent various vascular disorders, including endothelial dysfunction, vascular inflammation and vascular stiffness (Bondonno et al, 2016;Batko et al, 2019;Chen et al, 2019). Furthermore, excessive arginase activation can down-regulate NO production by reducing NOS availability through competition for their common substrate L-arginine (Bhatta et al, 2017;Zhou et al, 2018). This notion is supported by our results showing that HGWWD decreased endothelial arginase activity and aortic arginase 1 expression in STZ mice (Figure 4).…”

Section: Discussionsupporting

confidence: 74%

HuangqiGuizhiWuwu Decoction Prevents Vascular Dysfunction in Diabetes via Inhibition of Endothelial Arginase 1

et al. 2020

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Hyperglycemia induces vascular endothelial dysfunction, which contributes to the development of vascular complication of diabetes. A classic prescription of traditional medicine, HuangqiGuizhiWuwu Decoction (HGWWD) has been used for the treatment of various cardiovascular and cerebrovascular diseases, which all are related with vascular pathology. The present study investigated the effect of HGWWD treatment in streptozocin (STZ)-induced vascular dysfunction in mouse models. In vivo studies were performed using wild type mice as well as arginase 1 knockout specific in endothelial cells (EC-A1 −/−) of control mice, diabetes mice and diabetes mice treated with HGWWD (60 g crude drugs/kg/d) for 2 weeks. For in vitro studies, aortic tissues were treated with mice serum containing HGWWD with or without adenoviral arginase 1 (Ad-A1) transduction in high glucose (HG) medium. We found that HGWWD treatment restored STZ-induced impaired mean velocity and pulsatility index of mouse left femoral arteries, aortic pulse wave velocity and vascular endothelial relaxation accompanied by elevated NO production in the aorta and plasma, as well as reduced endothelial arginase activity and aortic arginase 1 expression. The protective effect of HGWWD is reversed by an inhibitor of nitric oxide synthesis. Meanwhile, the preventive effect of serum containing HGWWD in endothelial vascular dysfunction is completely blocked by Ad-A1 transduction in HG incubated aortas. HGWWD treatment further improved endothelial vascular dysfunction in STZ induced EC-A1 −/− mice. This study demonstrates that HGWWD improved STZ-induced vascular dysfunction through arginase 1-NO signaling, specifically targeting endothelial arginase 1.

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Section: Discussionsupporting

confidence: 74%

HuangqiGuizhiWuwu Decoction Prevents Vascular Dysfunction in Diabetes via Inhibition of Endothelial Arginase 1

et al. 2020

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“…2 There are complex pathways involved in the mechanisms of vascular calcification/aging in diabetes, including HG regulation in both endothelial and VSMC layers. 3,4,7,19 Vascular endothelial dysfunction is associated with diabetic conditions, 6,7,20 while little is known about the mechanisms driving calcification/senescence of VSMCs under diabetic conditions.…”

Section: Discussionmentioning

confidence: 99%

LncRNA‐ES3 inhibition by Bhlhe40 is involved in high glucose–induced calcification/senescence of vascular smooth muscle cells

Zhong

Cui

Zhan

et al. 2020

Annals of the New York Academy of Sciences

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Long noncoding RNAs (lncRNAs) have been investigated as novel regulatory molecules involved in diverse biological processes. Our previous study demonstrated that lncRNA‐ES3 is associated with the high glucose–induced calcification/senescence of human aortic vascular smooth muscle cells (HA‐VSMCs). However, the mechanism of lncRNA‐ES3 in vascular calcification/aging remained largely unknown. Here, we report that the expression of basic helix‐loop‐helix family member e40 (Bhlhe40) was decreased significantly in HA‐VSMCs treated with high glucose, whereas the expression of basic leucine zipper transcription factor (BATF) was increased. Overexpression of Bhlhe40 and inhibition of BATF alleviated calcification/senescence of HA‐VSMCs, as confirmed by Alizarin Red S staining and the presence of senescence‐associated β‐galactosidase–positive cells. Moreover, we identified that Bhlhe40 regulates lncRNA‐ES3 in HA‐VSMCs by binding to the promoter region of the lncRNA‐ES3 gene (LINC00458). Upregulation or inhibition of lncRNA‐ES3 expression significantly promoted or reduced calcification/senescence of HA‐VSMCs, respectively. Additionally, we identified that lncRNA‐ES3 functions in this process by suppressing the expression of miR‐95‐5p, miR‐6776‐5p, miR‐3620‐5p, and miR‐4747‐5p. The results demonstrate that lncRNA‐ES3 triggers gene silencing of multiple miRNAs by binding to Bhlhe40, leading to calcification/senescence of VSMCs. Our findings suggest that pharmacological interventions targeting lncRNA‐ES3 may be therapeutically beneficial in ameliorating vascular calcification/aging.

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“…44 Interestingly, arginase is up-regulated in erythrocytes in type 2 diabetes-an important comorbidity in patients with STEMI. 45,46 Accordingly, it was recently demonstrated that erythrocytes from both mice and patients with type 2 diabetes markedly impair recovery of cardiac systolic function, increase left ventricular end-diastolic pressure and increase infarct size following IR in comparison with erythrocytes from control mice or healthy humans. 46 The underlying mechanism behind this effect was increased arginase activity in erythrocytes which led to a decrease in NO production.…”

Section: Erythrocytesmentioning

confidence: 99%

Circulating blood cells and extracellular vesicles in acute cardioprotection

Davidson

Andreadou

Barile

et al. 2018

Cardiovascular Research

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During an ST-elevation myocardial infarction (STEMI), the myocardium undergoes a prolonged period of ischaemia. Reperfusion therapy is essential to minimize cardiac injury but can paradoxically cause further damage. Experimental procedures to limit ischaemia and reperfusion (IR) injury have tended to focus on the cardiomyocytes since they are crucial for cardiac function. However, there is increasing evidence that non-cardiomyocyte resident cells in the heart (as discussed in a separate review in this Spotlight series) as well as circulating cells and factors play important roles in this pathology. For example, erythrocytes, in addition to their main oxygen-ferrying role, can protect the heart from IR injury via the export of nitric oxide bioactivity. Platelets are well-known to be involved in haemostasis and thrombosis, but beyond these roles, they secrete numerous factors including sphingosine-1 phosphate (S1P), platelet activating factor, and cytokines that can all strongly influence the development of IR injury. This is particularly relevant given that most STEMI patients receive at least one type of platelet inhibitor. Moreover, there are large numbers of circulating vesicles in the blood, including microvesicles and exosomes, which can exert both beneficial and detrimental effects on IR injury. Some of these effects are mediated by the transfer of microRNA (miRNA) to the heart. Synthetic miRNA molecules may offer an alternative approach to limiting the response to IR injury. We discuss these and other circulating factors, focussing on potential therapeutic targets relevant to IR injury. Given the prevalence of comorbidities such as diabetes in the target patient population, their influence will also be discussed. This article is part of a Cardiovascular Research Spotlight Issue entitled 'Cardioprotection Beyond the Cardiomyocyte', and emerged as part of the discussions of the European Union (EU)-CARDIOPROTECTION Cooperation in Science and Technology (COST) Action, CA16225.

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Erythrocytes From Patients With Type 2 Diabetes Induce Endothelial Dysfunction Via Arginase I

Abstract: This study demonstrates a novel mechanism behind endothelial dysfunction in T2DM that is induced by RBC arginase I and ROS. Targeting arginase I in RBCs may serve as a novel therapeutic tool for the treatment of endothelial dysfunction in T2DM.

Cited by 141 publications

References 19 publications

HuangqiGuizhiWuwu Decoction Prevents Vascular Dysfunction in Diabetes via Inhibition of Endothelial Arginase 1

HuangqiGuizhiWuwu Decoction Prevents Vascular Dysfunction in Diabetes via Inhibition of Endothelial Arginase 1

LncRNA‐ES3 inhibition by Bhlhe40 is involved in high glucose–induced calcification/senescence of vascular smooth muscle cells

Circulating blood cells and extracellular vesicles in acute cardioprotection

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