Role of Arginase in Selective Impairment of Endothelium-Dependent Nitric Oxide Synthase-Mediated Dilation of Retinal Arterioles during Early Diabetes

Hein, Travis W.; Omae, Tsuneaki; Xu, Wei; Yoshida, Akitoshi; Li, Kuo

doi:10.1167/iovs.61.5.36

Cited by 11 publications

(13 citation statements)

References 51 publications

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“…Because the onset of hyperglycemia in db/db mice has been reported to be at 4 weeks of age 18 , it is likely that the deterioration of flow regulation might have begun at early diabetes around 4–6 weeks old. This speculation is supported by finding vasomotor dysregulation of both retinal arterioles 56 , 57 and venules 29 after induction of type 1 diabetes for only 2 weeks. Although the NO and arachidonic acid metabolites can participate in flicker-induced vasodilation 53 and increased retinal blood flow 54 , the mechanisms underlying neurovascular uncoupling and flow dysregulation in the diabetic retina are incompletely understood.…”

Section: Discussionmentioning

confidence: 89%

“…Although the NO and arachidonic acid metabolites can participate in flicker-induced vasodilation 53 and increased retinal blood flow 54 , the mechanisms underlying neurovascular uncoupling and flow dysregulation in the diabetic retina are incompletely understood. Interestingly, a recent study in diabetic pigs demonstrated the impairment of endothelium-dependent NO-mediated dilation of retinal arterioles by upregulated vascular arginase 57 , an enzyme that competes with NO synthase for their common substrate L-arginine, and thus consequently compromises NO production and vasodilation 58 . Because the vasodilation mediated by arachidonic acid 59 appears to be intact in retinal arterioles isolated from diabetic animals 57 , the observed retinal blood flow dysregulation in response to flicker light is likely due, in part, to NO deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, a recent study in diabetic pigs demonstrated the impairment of endothelium-dependent NO-mediated dilation of retinal arterioles by upregulated vascular arginase 57 , an enzyme that competes with NO synthase for their common substrate L-arginine, and thus consequently compromises NO production and vasodilation 58 . Because the vasodilation mediated by arachidonic acid 59 appears to be intact in retinal arterioles isolated from diabetic animals 57 , the observed retinal blood flow dysregulation in response to flicker light is likely due, in part, to NO deficiency. Nonetheless, contribution from other factors cannot be excluded because a progressive reduction of neuroretinal thickness and the loss of ganglion cells become apparent in db/db mice at 16- and 24-week of age 18 .…”

Section: Discussionmentioning

confidence: 99%

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Retinal blood flow dysregulation precedes neural retinal dysfunction in type 2 diabetic mice

Hanaguri

Yokota

Watanabe

et al. 2021

Sci Rep

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We investigated and compared the susceptibility of retinal blood flow regulation and neural function in mice developing type 2 diabetes. The longitudinal changes in retinal neuronal function and blood flow responses to a 10-min systemic hyperoxia and a 3-min flicker stimulation were evaluated every 2 weeks in diabetic db/db mice and nondiabetic controls (db/m) from age 8 to 20 weeks. The retinal blood flow and neural activity were assessed using laser speckle flowgraphy and electroretinography (ERG), respectively. The db/db mice had significantly higher blood glucose levels and body weight. The resting retinal blood flow was steady and comparable between two groups throughout the study. Hyperoxia elicited a consistent decrease, and flicker light an increase, in retinal blood flow in db/m mice independent of age. However, these flow responses were significantly diminished in db/db mice at 8 weeks old and then the mice became unresponsive to stimulations at 12 weeks. Subsequently, the ERG implicit time for oscillatory potential was significantly increased at 14 weeks of age while the a-wave and b-wave amplitudes and implicit times remained unchanged. The deficiencies of flow regulation and neurovascular coupling in the retina appear to precede neural dysfunction in the mouse with type 2 diabetes.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Retinal blood flow dysregulation precedes neural retinal dysfunction in type 2 diabetic mice

Hanaguri

Yokota

Watanabe

et al. 2021

Sci Rep

Self Cite

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“…First of all, a significantly reduced Arginine concentration was shown. It may be caused by shunting the L-Arginine from the eNOS to the arginase pathway with its enhanced arginase degradation, as an increased ornithine to Arginine ratio in plasma was found [ 18 , 22 , 23 ]. It is noteworthy that the results are in accordance with the studies by Shemyakin et al, proving that the downregulation of arginase improves endothelial function among patients with DM and may become a promising therapeutic target [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

A Cross-Talk between the Erythrocyte L-Arginine/ADMA/Nitric Oxide Metabolic Pathway and the Endothelial Function in Subjects with Type 2 Diabetes Mellitus

et al. 2021

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(1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are extensively studied, the alterations in the nitric-oxide-metabolic-pathway require further investigations. Additionally, the role of erythrocytes in the vascular tone regulation has not been extensively explored. The aim of this study was to evaluate the endothelial-function and the nitric-oxide-metabolic-pathway in erythrocytes and plasma of diabetic individuals. (2) Methods: A total of 80 subjects were enrolled in this cross-sectional study, including 35 patients with DM and 45 healthy individuals. The endothelial-function was evaluated in response to different stimuli. (3) Results: In the DM group, decreased Arginine and citrulline concentrations in the plasma compartment with reduced Arginine/ADMA and ADMA/DMA-ratios were observed. Preserved nitric-oxide-metabolism in erythrocytes with reduced citrulline level and significantly higher NO-bioavailability were noted. Significant endothelial dysfunction in DM individuals was proved in response to the heat-stimulus. (4) Conclusions: DM patients at an early stage of disease show significant differences in the nitric-oxide-metabolic-pathway, which are more pronounced in the plasma compartment. Erythrocytes constitute a buffer with a higher nitric-oxide-bioavailability, less affected by the DM-related deviations. Patients at an early-stage of DM reveal endothelial-dysfunction, which could be diagnosed earlier using the laser-Doppler-flowmetry.

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“…This finding is consistent with a previous study showing that PKCβ2 activation links to the impairment of flow-induced vasodilation in a microvascular network by suppression of NO release from the endothelium [ 52 ]. Interestingly, inhibition of PKCβ2 preserves endothelium-dependent vasodilation [ 53 ] and reverses endothelial barrier dysfunction [ 54 ] in experimental models with hyperglycemia and diabetes, which are known to cause endothelial NO deficiency [ 14 , 23 , 52 , 55 ]. It should be noted that PKCβ2 is expressed abundantly in the coronary arteriolar wall, including endothelial cells, and is co-localized with eNOS ( Figure 5 ).…”

Section: Discussionmentioning

confidence: 99%

Activation of Coronary Arteriolar PKCβ2 Impairs Endothelial NO-Mediated Vasodilation: Role of JNK/Rho Kinase Signaling and Xanthine Oxidase Activation

Thengchaisri

Hein

Ren

et al. 2021

IJMS

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Protein kinase C (PKC) activation can evoke vasoconstriction and contribute to coronary disease. However, it is unclear whether PKC activation, without activating the contractile machinery, can lead to coronary arteriolar dysfunction. The vasoconstriction induced by the PKC activator phorbol 12,13-dibutyrate (PDBu) was examined in isolated porcine coronary arterioles. The PDBu-evoked vasoconstriction was sensitive to a broad-spectrum PKC inhibitor but not affected by inhibiting PKCβ2 or Rho kinase. After exposure of the vessels to a sub-vasomotor concentration of PDBu (1 nmol/L, 60 min), the endothelium-dependent nitric oxide (NO)-mediated dilations in response to serotonin and adenosine were compromised but the dilation induced by the NO donor sodium nitroprusside was unaltered. PDBu elevated superoxide production, which was blocked by the superoxide scavenger Tempol. The impaired NO-mediated vasodilations were reversed by Tempol or inhibition of PKCβ2, xanthine oxidase, c-Jun N-terminal kinase (JNK) and Rho kinase but were not affected by a hydrogen peroxide scavenger or inhibitors of NAD(P)H oxidase and p38 kinase. The PKCβ2 protein was detected in the arteriolar wall and co-localized with endothelial NO synthase. In conclusion, activation of PKCβ2 appears to compromise NO-mediated vasodilation via Rho kinase-mediated JNK signaling and superoxide production from xanthine oxidase, independent of the activation of the smooth muscle contractile machinery.

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Role of Arginase in Selective Impairment of Endothelium-Dependent Nitric Oxide Synthase-Mediated Dilation of Retinal Arterioles during Early Diabetes

Abstract: of arginase in selective impairment of endothelium-dependent nitric oxide synthase-mediated dilation of retinal arterioles during early diabetes.

Cited by 11 publications

References 51 publications

Retinal blood flow dysregulation precedes neural retinal dysfunction in type 2 diabetic mice

Retinal blood flow dysregulation precedes neural retinal dysfunction in type 2 diabetic mice

A Cross-Talk between the Erythrocyte L-Arginine/ADMA/Nitric Oxide Metabolic Pathway and the Endothelial Function in Subjects with Type 2 Diabetes Mellitus

Activation of Coronary Arteriolar PKCβ2 Impairs Endothelial NO-Mediated Vasodilation: Role of JNK/Rho Kinase Signaling and Xanthine Oxidase Activation

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