Dopamine D4 receptor protected against hyperglycemia-induced endothelial dysfunction via PI3K /eNOS pathway

He, Wei; Yao, Yong-Gang; Liu, Juncheng; Cao, Yihan; Si, Chunying; Zheng, Rongfei; Zeng, Chunyu; Huaimin, Guan; Li, Ling

doi:10.1016/j.bbrc.2019.08.080

Cited by 8 publications

(5 citation statements)

References 36 publications

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“…The DA-induced suppression of NF-κΒ and STAT3 activity is not specific only to endothelial cells, as it has also been demonstrated in other cells, including chondrocytes, glioma cells, and hepatocytes [ 96 , 97 , 98 ]. Moreover, the protective effects of DA on endothelial cells might also include other mechanisms that were not tested in this study, but were reported previously, such as inhibition of apoptosis, oxidative stress [ 99 , 100 ], VEGF receptor 2, focal adhesion kinase, and MAPK in endothelial cells [ 101 ], as well as suppression of microvascular hyperpermeability, angiogenesis, proliferation, and migration of endothelial cells [ 102 ].…”

Section: Discussionmentioning

confidence: 87%

Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex

Štofková

Zloh

Andreanska

et al. 2021

IJMS

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The gateway reflex is a mechanism by which neural inputs regulate chemokine expression at endothelial cell barriers, thereby establishing gateways for the invasion of autoreactive T cells into barrier-protected tissues. In this study, we hypothesized that rod photoreceptor dysfunction causes remodeling of retinal neural activity, which influences the blood–retinal barrier and the development of retinal inflammation. We evaluated this hypothesis using Gnat1rd17 mice, a model of night blindness with late-onset rod-cone dystrophy, and experimental autoimmune uveoretinitis (EAU). Retinal remodeling and its effect on EAU development were investigated by transcriptome profiling, target identification, and functional validation. We showed that Gnat1rd17 mice primarily underwent alterations in their retinal dopaminergic system, triggering the development of an exacerbated EAU, which was counteracted by dopamine replacement with L-DOPA administered either systemically or locally. Remarkably, dopamine acted on retinal endothelial cells to inhibit NF-κB and STAT3 activity and the expression of downstream target genes such as chemokines involved in T cell recruitment. These results suggest that rod-mediated dopamine release functions in a gateway reflex manner in the homeostatic control of immune cell entry into the retina, and the loss of retinal dopaminergic activity in conditions associated with rod dysfunction increases the susceptibility to autoimmune uveitis.

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Section: Discussionmentioning

confidence: 87%

Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex

Štofková

Zloh

Andreanska

et al. 2021

IJMS

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“…Dopaminergic pathways are one of the regulators of autoimmune reactions [7] , with D2-like receptors playing a role in diabetes [22] . Therefore, we have investigated the association between the −521C>T DRD4 gene polymorphism and the risk of DM1 and its comorbidities.…”

Section: Discussionmentioning

confidence: 99%

Variation in the Dopamine-4-Receptor Gene in Patients with Type 1 Diabetes

Słomiński¹,

Skrzypkowska²,

Myśliwiec³

et al. 2023

Neuroendocrinology

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IIntroduction Because dopaminergic signaling pathways are one of the regulators of autoimmunity, we hypothesize that the -521C>T DRD4 gene polymorphism may correlate with the risk of diabetes mellitus type 1 (DM1) and its comorbidities. Methods The connection of the -521C>T DRD4 gene polymorphism with the DM1 and its comorbidities as well as the levels of serum pro- and anti-inﬂammatory markers, lipid profiles and values of monocyte subsets was evaluated. Results The key results of our study are as follows: 1) CC genotype and C allele are associated with a reduced risk of DM1 development (OR = 0.593, p = 0.005 and OR = 0.725, p = 0.003; resp.) whereas TT genotype and T allele are associated with a higher risk of DM1 (OR = 1.408, p = 0.04 and OR = 1.380, p = 0.003; resp.); 2) CC genotype is associated with an increased risk of dyslipidemia and retinopathy in diabetic patients (OR = 2.376, p = 0.001 and OR = 2.111, p = 0.01; resp.); 3) CC genotype and C allele carriers had the highest frequency of pro-inflammatory CD16+ monocytes (p = 2*10-4 and 0.04 resp.); 4) the DRD4 -521C>T polymorphism modifies the inflammatory status as well as lipid profile in DM1 patients. Discussion/Conclusion Our data imply that the dopaminergic signaling pathways may play an important role in the etiology of DM1 as well as its comorbidities and will provide a new insight into the DM1 risk management. The -521C>T DRD4 gene polymorphism could be considered a genetic marker to predict susceptibility to DM1 as well as retinopathy and dyslipidemia progress in patients with already established disease.

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“…Haloperidol, a D2 receptor antagonist, prevented this effect. Wang et al [ 59 ] reported that the protective effect of DA against endothelial dysfunction was also mediated through D4 receptors. Clinical and experimental studies showed that DA could directly increase basal local CBF, and this increase is blocked by haloperidol [ 29 , 60 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

Cerebral Blood Flow in Predator Stress-Resilient and -Susceptible Rats and Mechanisms of Resilience

Kondashevskaya

Downey

Tseĭlikman

et al. 2022

IJMS

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Stress-induced conditions are associated with impaired cerebral blood flow (CBF) and increased risk of dementia and stroke. However, these conditions do not develop in resilient humans and animals. Here the effects of predator stress (PS, cat urine scent, ten days) on CBF and mechanisms of CBF regulation were compared in PS-susceptible (PSs) and PS-resilient (PSr) rats. Fourteen days post-stress, the rats were segregated into PSs and PSr groups based on a behavior-related anxiety index (AI). CBF and its endothelium-dependent changes were measured in the parietal cortex by laser Doppler flowmetry. The major findings are: (1) PS susceptibility was associated with reduced basal CBF and endothelial dysfunction. In PSr rats, the basal CBF was higher, and endothelial dysfunction was attenuated. (2) CBF was inversely correlated with the AI of PS-exposed rats. (3) Endothelial dysfunction was associated with a decrease in eNOS mRNA in PSs rats compared to the PSr and control rats. (4) Brain dopamine was reduced in PSs rats and increased in PSr rats. (5) Plasma corticosterone of PSs was reduced compared to PSr and control rats. (6) A hypercoagulation state was present in PSs rats but not in PSr rats. Thus, potential stress resilience mechanisms that are protective for CBF were identified.

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Dopamine D4 receptor protected against hyperglycemia-induced endothelial dysfunction via PI3K /eNOS pathway

Cited by 8 publications

References 36 publications

Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex

Depletion of Retinal Dopaminergic Activity in a Mouse Model of Rod Dysfunction Exacerbates Experimental Autoimmune Uveoretinitis: A Role for the Gateway Reflex

Variation in the Dopamine-4-Receptor Gene in Patients with Type 1 Diabetes

Cerebral Blood Flow in Predator Stress-Resilient and -Susceptible Rats and Mechanisms of Resilience

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