p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

Yu, Yi; Rajapakse, Angana Gupta; Montani, Jean‐Pierre; Yang, Zhihong; Ming, Xiu‐Fen

doi:10.1186/preaccept-1124727874129820

Cited by 19 publications

(29 citation statements)

References 22 publications

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“…Furthermore, in scratch assays, we found that IL-6 stimulated fibroblast migration and that this IL-6-stimulated migration was blocked by the selective p38 MAPK inhibitor SB203580, confirming the involvement of p38 MAPK pathways in non-diabetic fibroblast activity. MAPKs are known to be involved in inflammation, cell proliferation, migration, and differentiation, and several reports have confirmed the role of the p38 pathway in influencing the migration of different cell types [50–56]. Our study therefore demonstrates that IL-6-induced fibroblast migration requires p38 MAPK and Akt activation, and that this effect is impaired in diabetic fibroblasts.…”

Section: Discussionsupporting

confidence: 78%

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice

et al. 2017

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Persistent inflammatory environment and abnormal macrophage activation are characteristics of chronic diabetic wounds. Here, we attempted to characterize the differences in macrophage activation and temporal variations in cytokine expression in diabetic and non-diabetic wounds, with a focus on interleukin (IL)-6 mRNA expression and the p38 MAPK and PI3K/Akt signaling pathways. Cutaneous wound closure, CD68- and arginase-1 (Arg-1)-expressing macrophages, and cytokine mRNA expression were examined in non-diabetic and streptozotocin-induced type 1 diabetic mice at different time points after injury. The effect of IL-6 on p38 MAPK and Akt phosphorylation was investigated, and an in vitro scratch assay was performed to determine the role of IL-6 in primary skin fibroblast migration. Before injury, mRNA expression levels of the inflammatory markers iNOS, IL-6, and TNF-α were higher in diabetic mice; however, IL-6 expression was significantly lower 6 h post injury in diabetic wounds than that in non-diabetic wounds. Non-diabetic wounds exhibited increased p38 MAPK and Akt phosphorylation; however, no such increase was found in diabetic wounds. In fibroblasts from non-diabetic mice, IL-6 increased the phosphorylation of p38 MAPK and levels of its downstream factor CREB, and also significantly increased Akt phosphorylation and levels of its upstream factor P13K. These effects of IL-6 were not detected in fibroblasts derived from the diabetic mice. In scratch assays, IL-6 stimulated the migration of primary cultured skin fibroblasts from the non-diabetic mice, and the inhibition of p38 MAPK was found to markedly suppress IL-6–stimulated fibroblast migration. These findings underscore the critical differences between diabetic and non-diabetic wounds in terms of macrophage activation, cytokine mRNA expression profile, and involvement of the IL-6-stimulated p38 MAPK–Akt signaling pathway. Aberrant macrophage activation and abnormalities in the cytokine mRNA expression profile during different phases of wound healing should be addressed when designing effective therapeutic modalities for refractory diabetic wounds.

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Section: Discussionsupporting

confidence: 78%

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice

et al. 2017

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“…25 An arginase inhibitor has been shown to protect against endothelial dysfunction caused by ischemia reperfusion in patients with CAD. 30 Recent reports have implicated A2 in endothelial dysfunction through endothelial nitric oxide synthase (eNOS) uncoupling in obese and aged mice, 32, 33 as well as in impairment of cerebral blood flow after TBI. 34 In addition, recent studies from our laboratory have demonstrated the involvement of A2 in neurovascular damage in a neonatal mouse model of ischemic retinopathy.…”

Section: Discussionmentioning

confidence: 99%

“…31 Upregulation of A2 has also been implicated in vascular dysfunction associated with aging, obesity and retinopathy. 19, 20, 32, 33 Previous reports have shown that A2 expression increases after traumatic brain injury (TBI) and that TBI-induced impairment of cerebral blood flow is prevented by A2 deletion. 34 These studies along with our previous studies underscore a crucial role for A2 in central nervous system injury.…”

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confidence: 99%

Arginase 2 promotes neurovascular degeneration during ischemia/reperfusion injury

Shosha

Yokota

et al. 2016

Cell Death Dis

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Retinal ischemia is a major cause of visual impairment and blindness and is involved in various disorders including diabetic retinopathy, glaucoma, optic neuropathies and retinopathy of prematurity. Neurovascular degeneration is a common feature of these pathologies. Our lab has previously reported that the ureahydrolase arginase 2 (A2) is involved in ischemic retinopathies. Here, we are introducing A2 as a therapeutic target to prevent neurovascular injury after retinal ischemia/reperfusion (I/R) insult. Studies were performed with mice lacking both copies of A2 (A2−/−) and wild-type (WT) controls (C57BL6J). I/R insult was conducted on the right eye and the left eye was used as control. Retinas were collected for analysis at different times (3 h–4 week after injury). Neuronal and microvascular degeneration were evaluated using NeuN staining and vascular digests, respectively. Glial activation was evaluated by glial fibrillary acidic protein expression. Necrotic cell death was studied by propidium iodide labeling and western blot for RIP-3. Arginase expression was determined by western blot and quantitative RT-PCR. Retinal function was determined by electroretinography (ERG). A2 mRNA and protein levels were increased in WT I/R. A2 deletion significantly reduced ganglion cell loss and microvascular degeneration and preserved retinal morphology after I/R. Glial activation, reactive oxygen species formation and cell death by necroptosis were significantly reduced by A2 deletion. ERG showed improved positive scotopic threshold response with A2 deletion. This study shows for the first time that neurovascular injury after retinal I/R is mediated through increased expression of A2. Deletion of A2 was found to be beneficial in reducing neurovascular degeneration after I/R.

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“…In addition to PVAT NO, NO production from the endothelium is also reduced in experimental obesity (Korda et al, ; Marchesi et al, ; Yu et al, ).…”

Section: Dysregulation Of Pvat‐derived Vasoregulators In Obesitymentioning

confidence: 99%

The role of perivascular adipose tissue in obesity‐induced vascular dysfunction

Xia

2016

British J Pharmacology

145

128

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Under physiological conditions, perivascular adipose tissue (PVAT) attenuates agonist‐induced vasoconstriction by releasing vasoactive molecules including hydrogen peroxide, angiotensin 1–7, adiponectin, methyl palmitate, hydrogen sulfide, NO and leptin. This anticontractile effect of PVAT is lost under conditions of obesity. The central mechanism underlying this PVAT dysfunction in obesity is likely to be an ‘obesity triad’ (consisting of PVAT hypoxia, inflammation and oxidative stress) that leads to the impairment of PVAT‐derived vasoregulators. The production of hydrogen sulfide, NO and adiponectin by PVAT is reduced in obesity, whereas the vasodilator response to leptin is impaired (vascular leptin resistance). Strikingly, the vasodilator response to acetylcholine is reduced only in PVAT‐containing, but not in PVAT‐free thoracic aorta isolated from diet‐induced obese mice, indicating a unique role for PVAT in obesity‐induced vascular dysfunction. Furthermore, PVAT dysfunction has also been observed in small arteries isolated from the gluteal/visceral fat biopsy samples of obese individuals. Therefore, PVAT may represent a new therapeutic target for vascular complications in obesity. A number of approaches are currently being tested under experimental conditions. Potential therapeutic strategies improving PVAT function include body weight reduction, enhancing PVAT hydrogen sulfide release (e.g. rosiglitazone, atorvastatin and cannabinoid CB1 receptor agonists) and NO production (e.g. arginase inhibitors), inhibition of the renin–angiotensin–aldosterone system, inhibition of inflammation with melatonin or cytokine antagonists, activators of AMP‐activated kinase (e.g. metformin, resveratrol and diosgenin) and adiponectin releasers or expression enhancers.Linked ArticlesThis article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue – Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc

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p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

Cited by 19 publications

References 22 publications

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice

Interleukin-6 stimulates Akt and p38 MAPK phosphorylation and fibroblast migration in non-diabetic but not diabetic mice

Arginase 2 promotes neurovascular degeneration during ischemia/reperfusion injury

The role of perivascular adipose tissue in obesity‐induced vascular dysfunction

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