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Influence of bradykinin B2 receptor and dopamine D2 receptor on the oxidative stress, inflammatory response, and apoptotic process in human endothelial cells.

ABSTRACT: Endothelial dysfunction is a hallmark of a wide range of cardiovascular diseases and is often linked to oxidative stress and inflammation. Our earlier study reported the formation of a functional heterodimer between bradykinin receptor 2 (B2R) and dopamine receptor 2 (D2R) that may modulate cell responses, dependent on intracellular signaling. Here, for the first time, we showed a cooperative effect of these receptors on the modulation of processes involved in oxidative stress, inflammation, and apoptosis in endothelial cells. Sumanirole, a specific D2R agonist, was shown to diminish the excessive production of reactive oxygen species induced by bradykinin, a proinflammatory B2R-activating peptide. This effect was accompanied by modified activities of antioxidant enzymes and increased phosphorylation of endothelial nitric oxide synthase, leading to enhance NO production. In turn, endothelial cell co-stimulation with B2R and D2R agonists inhibited the release of interleukin-6 and endothelin-1 and modulated the expression of apoptosis markers, such as Bcl-2, Bcl-xL, Bax, and caspase 3/7 activity. All these observations argue that the D2R agonist counteracts the pro-oxidative, pro-inflammatory, and pro-apoptotic effects induced through B2R, finally markedly improving endothelial functions.

SUBMITTER: Niewiarowska-Sendo A

PROVIDER: S-EPMC6241119 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Influence of bradykinin B2 receptor and dopamine D2 receptor on the oxidative stress, inflammatory response, and apoptotic process in human endothelial cells.

Niewiarowska-Sendo Anna A Kozik Andrzej A Guevara-Lora Ibeth I

PloS one 20181114 11

Endothelial dysfunction is a hallmark of a wide range of cardiovascular diseases and is often linked to oxidative stress and inflammation. Our earlier study reported the formation of a functional heterodimer between bradykinin receptor 2 (B2R) and dopamine receptor 2 (D2R) that may modulate cell responses, dependent on intracellular signaling. Here, for the first time, we showed a cooperative effect of these receptors on the modulation of processes involved in oxidative stress, inflammation, and ...[more]

PMID: 30427893

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Project description:Bradykinin B2 receptor (B2R) and angiotensin-(1-7) Mas receptor (MasR)-mediated effects are physiologically interconnected. The molecular basis for such cross talk is unknown. It is hypothesized that the cross talk occurs at the receptor level. We investigated B2R-MasR heteromerization and the functional consequences of such interaction. B2R fused to the cyan fluorescent protein and MasR fused to the yellow fluorescent protein were transiently coexpressed in human embryonic kidney293T cells. Fluorescence resonance energy transfer analysis showed that B2R and MasR formed a constitutive heteromer, which was not modified by their agonists. B2R or MasR antagonists decreased fluorescence resonance energy transfer efficiency, suggesting that the antagonist promoted heteromer dissociation. B2R-MasR heteromerization induced an 8-fold increase in the MasR ligand-binding affinity. On agonist stimulation, the heteromer was internalized into early endosomes with a slower sequestration rate from the plasma membrane, compared with single receptors. B2R-MasR heteromerization induced a greater increase in arachidonic acid release and extracellular signal-regulated kinase phosphorylation after angiotensin-(1-7) stimulation, and this effect was blocked by the B2R antagonist. Concerning serine/threonine kinase Akt activity, a significant bradykinin-promoted activation was detected in B2R-MasR but not in B2R-expressing cells. Angiotensin-(1-7) and bradykinin elicited antiproliferative effects only in cells expressing B2R-MasR heteromers, but not in cells expressing each receptor alone. Proximity ligation assay confirmed B2R-MasR interaction in human glomerular endothelial cells supporting the interaction between both receptors in vivo. Our findings provide an explanation for the cross talk between bradykinin B2R and angiotensin-(1-7) MasR-mediated effects. B2R-MasR heteromerization induces functional changes in the receptor that may lead to long-lasting protective properties.

Dataset Information

Influence of bradykinin B2 receptor and dopamine D2 receptor on the oxidative stress, inflammatory response, and apoptotic process in human endothelial cells.

Publications

Influence of bradykinin B2 receptor and dopamine D2 receptor on the oxidative stress, inflammatory response, and apoptotic process in human endothelial cells.

Similar Datasets

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