A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth

Couto, Javier; Ayturk, Ugur M.; Konczyk, Dennis J.; Goss, Jeremy A.; Huang, August Yue; Hann, Steve; Reeve, Jennifer; Liang, Marilyn G.; Bischoff, Joyce; Warman, Matthew L.; Greene, Arin K.

doi:10.1007/s10456-016-9538-1

Cited by 102 publications

(83 citation statements)

References 14 publications

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“…Consistently with our findings, previous studies have reported that NR4A1 activation was noted in fatty liver disease and atherosclerosis [24,25] and that the genetic deletion of NR4A1 or pharmacological inhibition of NR4A1 retards or prevents the progression of nonalcoholic fatty liver and atherosclerosis [66,67]. Collectively, these observations have demonstrated the sufficiency of NR4A1 to exacerbate chronic metabolic diseases, which may highlight a new method for treating chronic metabolic disorders by targeting NR4A1.…”

Section: Discussionsupporting

confidence: 80%

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

Sheng

Dai

et al. 2018

Cell Physiol Biochem

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Background/Aims: Disrupted mitochondrial dynamics, including excessive mitochondrial fission and mitophagy arrest, has been identified as a pathogenic factor in diabetic nephropathy (DN), although the upstream regulatory signal for mitochondrial fission activation and mitophagy arrest in the setting of DN remains unknown. Methods: Wild-type (WT) mice and NR4A1 knockout (NR4A1-KO) mice were used to establish a DN model. Mitochondrial fission and mitophagy were evaluated by western blotting and immunofluorescence. Mitochondrial function was assessed by JC-1 staining, the mPTP opening assay, immunofluorescence and western blotting. Renal histopathology and morphometric analyses were conducted via H&E, Masson and PASM staining. Kidney function was evaluated via ELISA, western blotting and qPCR. Results: In the present study, we found that nuclear receptor subfamily 4 group A member 1 (NR4A1) was actually activated by a chronic hyperglycemic stimulus. Higher NR4A1 expression was associated with glucose metabolism disorder, renal dysfunction, kidney hypertrophy, renal fibrosis, and glomerular apoptosis. At the molecular level, increased NR4A1 expression activated p53, and the latter selectively stimulated mitochondrial fission and inhibited mitophagy by modulating Mff and Parkin transcription. Excessive Mff-related mitochondrial fission caused mitochondrial oxidative stress, promoted mPTP opening, exacerbated proapoptotic protein leakage into the cytoplasm, and finally initiated mitochondria-dependent cellular apoptosis in the setting of diabetes. In addition, defective Parkin-mediated mitophagy repressed cellular ATP production and failed to correct the uncontrolled mitochondrial fission. However, NR4A1 knockdown interrupted the Mff-related mitochondrial fission and recused Parkin-mediated mitophagy, reducing the hyperglycemia-mediated mitochondrial damage and thus improving renal function. Conclusion: Overall, we have shown that NR4A1 functions as a novel malefactor in diabetic renal damage and operates by synchronously enhancing Mff-related mitochondrial fission and repressing Parkin-mediated mitophagy. Thus, finding strategies to regulate the balance of the NR4A1-p53 signaling pathway and mitochondrial homeostasis may be a therapeutic option for treating diabetic nephropathy in clinical practice.

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Section: Discussionsupporting

confidence: 80%

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

Sheng

Dai

et al. 2018

Cell Physiol Biochem

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“…Next, experiments were carried out to analyze the mechanism by which melatonin blocked CypD phosphorylation in the context of microvascular IR injury. PGAM5, the mitochondrial serine/threonine protein phosphatase, has been well‐recognized as a major factor controlling necroptosis via multiple mechanisms . At the molecular level, PGAM5 evokes excessive Drp1‐related mitochondrial fission via modifying Drp1 phosphorylation on serine 637 .…”

Section: Resultsmentioning

confidence: 99%

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

Zhou

Zhu

et al. 2018

Journal of Pineal Research

193

168

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The molecular features of necroptosis in cardiac ischemia-reperfusion (IR) injury have been extensively explored. However, there have been no studies investigating the physiological regulatory mechanisms of melatonin acting on necroptosis in cardiac IR injury. This study was designed to determine the role of necroptosis in microvascular IR injury, and investigate the contribution of melatonin in repressing necroptosis and preventing IR-mediated endothelial system collapse. Our results demonstrated that Ripk3 was primarily activated by IR injury and consequently aggravated endothelial necroptosis, microvessel barrier dysfunction, capillary hyperpermeability, the inflammation response, microcirculatory vasospasms, and microvascular perfusion defects. However, administration of melatonin prevented Ripk3 activation and provided a pro-survival advantage for the endothelial system in the context of cardiac IR injury, similar to the results obtained via genetic ablation of Ripk3. Functional investigations clearly illustrated that activated Ripk3 upregulated PGAM5 expression, and the latter increased CypD phosphorylation, which obligated endothelial cells to undergo necroptosis via augmenting mPTP (mitochondrial permeability transition pore) opening. Interestingly, melatonin supplementation suppressed mPTP opening and interrupted endothelial necroptosis via blocking the Ripk3-PGAM5-CypD signal pathways. Taken together, our studies identified the Ripk3-PGAM5-CypD-mPTP axis as a new pathway responsible for reperfusion-mediated microvascular damage via initiating endothelial necroptosis. In contrast, melatonin treatment inhibited the Ripk3-PGAM5-CypD-mPTP cascade and thus reduced cellular necroptosis, conferring a protective advantage to the endothelial system in IR stress. These findings establish a new paradigm in microvascular IR injury and update the concept for cell death management handled by melatonin under the burden of reperfusion attack.

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“…) and GNA11 (Couto et al . ) in mediating angiogenesis. In addition, double knockdown of GNAq and 11 in HUVECs blocks VEGFA‐induced cell migration (Zeng et al .…”

Section: Discussionmentioning

confidence: 99%

“…More recently, Couto et al . () reported that a somatic mutation of GNA11 is associated with capillary malformation in human. These data suggest the importance of GNA11 with respect to mediating endothelial function, possibly depending on the origins of endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

GNA11 differentially mediates fibroblast growth factor 2‐ and vascular endothelial growth factor A‐induced cellular responses in human fetoplacental endothelial cells

Zou

Zhao

et al. 2018

The Journal of Physiology

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During pregnancy, fetoplacental angiogenesis is dramatically increased in association with rapidly elevated blood flow. Any disruption of fetoplacental angiogenesis may lead to pregnancy complications such as intrauterine growth restriction. Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor A (VEGFA) are crucial regulators of fetoplacental angiogenesis. G protein α subunits q (GNAq) and 11 (GNA11) are two members of the Gα subfamily involved in mediating vascular growth and basal blood pressure. However, little is known about the roles of GNA11 alone with respect to mediating the FGF2- and VEGFA-induced fetoplacental endothelial function. Using a cell model of human umbilical cord vein endothelial cells cultured under physiological chronic low O (3% O ), we showed that GNA11 small interfering RNA (siRNA) dramatically inhibited (P < 0.05) FGF2- and VEGFA-stimulated fetoplacental endothelial migration (by ∼36% and ∼50%, respectively) but not proliferation and permeability. GNA11 siRNA also elevated (P < 0.05) FGF2- and VEGFA-induced phosphorylation of phospholipase C-β3 (PLCβ3) at S537 in a time-dependent fashion but not mitogen-activated protein kinase 3/1 (ERK1/2) and v-akt murine thymoma viral oncogene homologue 1 (AKT1). These data suggest that GNA11 mediates FGF2- and VEGFA-stimulated fetoplacental endothelial cell migration partially via altering the activation of PLCβ3.

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A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth

Cited by 102 publications

References 14 publications

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

Inhibitory effect of melatonin on necroptosis via repressing the Ripk3‐PGAM5‐CypD‐mPTP pathway attenuates cardiac microvascular ischemia–reperfusion injury

GNA11 differentially mediates fibroblast growth factor 2‐ and vascular endothelial growth factor A‐induced cellular responses in human fetoplacental endothelial cells

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