p38 Mitogen-Activated Protein Kinase Is Required for Glucosamine-Induced Endothelial Nitric Oxide Synthase Uncoupling and Plasminogen-Activator Inhibitor Expression

Wu, Zongsong; Xiong, Yuyan; Gajanayake, Thusitha; Ming, Xiu‐Fen; Yang, Zhihong

doi:10.1253/circj.cj-12-0016

Cited by 8 publications

(11 citation statements)

References 51 publications

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“…Moreover, rapamycin and resveratrol which are capable of inhibiting mTORC1-S6K1 signaling pathway can also inhibit arginase activity and recouples eNOS function in aging animal models (Rajapakse et al, 2011; Yepuri et al, 2012). Furthermore, p38MAPK inhibitors have been shown to improve endothelial function also through inhibition of eNOS-uncoupling in endothelial cells or mouse aortas exposed to glucosamine (Wu et al, 2012) or inhibition of arginase in the corpora cavernosa from angiotensin-II-treated mice (Toque et al, 2010). Recently, a small clinical study has also showed that p38MAPK inhibitors improves endothelial function and reduces systemic and vascular inflammation in patients with hypercholesterolemia and coronary artery disease (Cheriyan et al, 2011; Elkhawad et al, 2012).…”

Section: Perspectives Of Targeting Arginase In Cardiovascular Diseasesmentioning

confidence: 99%

Arginase: The Emerging Therapeutic Target for Vascular Oxidative Stress and Inflammation

2013

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Oxidative stress and inflammation in the vascular wall are essential mechanisms of atherosclerosis and vascular dysfunctions associated with risk factors such as metabolic diseases, aging, hypertension, etc. Evidence has been provided that activation of the vascular endothelial cells in the presence of the risk factors promotes oxidative stress and vascular inflammatory responses, leading to acceleration of atherosclerotic vascular disease. Increasing number of studies from recent years demonstrates that uncoupling of endothelial nitric oxide synthase (eNOS), whereby the enzyme eNOS produces detrimental amount of superoxide anion O2MathClass-bin− instead the vasoprotective nitric oxide (NO⋅), plays a critical role in vascular dysfunction under various pathophysiological conditions and in aging. The mechanisms of eNOS-uncoupling seem multiple and complex. Recent research provides emerging evidence supporting an essential role of increased activity of arginases including arginase-I and arginase-II in causing eNOS-uncoupling, which results in vascular oxidative stress and inflammatory responses, and ultimately leading to vascular diseases. This review article will summarize the most recent findings on the functional roles of arginases in vascular diseases and/or dysfunctions and the underlying mechanisms in relation to oxidative stress and inflammations. Moreover, regulatory mechanisms of arginases in the vasculature are reviewed and the future perspectives of targeting arginases as therapeutic options in vascular diseases are discussed.

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Section: Perspectives Of Targeting Arginase In Cardiovascular Diseasesmentioning

confidence: 99%

Arginase: The Emerging Therapeutic Target for Vascular Oxidative Stress and Inflammation

2013

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“…The HBP is associated with vasodilation and the ET-1-induced vasoconstriction response (52,53). HBP activated by excess glucosamine causes endothelial nitric oxide synthase uncoupling to decrease nitric oxide production in isolated mouse aortas, this effect impaired endothelium-dependent relaxations finally (52).…”

Section: Discussionmentioning

confidence: 99%

“…HBP activated by excess glucosamine causes endothelial nitric oxide synthase uncoupling to decrease nitric oxide production in isolated mouse aortas, this effect impaired endothelium-dependent relaxations finally (52). Furthermore, ET-1 increases glycosylation with β-N-acetylglucosamine in vascular smooth muscle cells, which increases vascular contractile responses (53).…”

Section: Discussionmentioning

confidence: 99%

Quercetin alleviates cell apoptosis and inflammation via the ER stress pathway in vascular endothelial cells cultured in high concentrations of glucosamine

Cai

Bao

Ding

et al. 2016

Molecular Medicine Reports

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Abstract.Glucosamine is a possible cause of vascular endothelial injury in the initial stages of atherosclerosis, through endoplasmic reticulum (ER) stress resulting in fatty streaks in the vascular wall. Quercetin is an anti-diabetic and cardiovascular protective agent that has previously been demonstrated to reduce ER stress in human umbilical vein endothelial cells (HUVECs). The present study aimed to investigate whether quercetin prevents glucosamine-induced apoptosis and inflammation via ER stress pathway in HUVECs. The effect of quercetin on cell viability, apoptosis, and protein expression levels of inflammatory cytokines and ER stress markers was investigated in glucosamine-supplemented HUVECs. Quercetin was demonstrated to protect against glucosamine-induced apoptosis, improved cell viability, and inhibited expression of pro-inflammatory factors and endothelin-1. Quercetin treatment also reduced the expression levels of glucose-regulated protein 78, phosphorylated protein kinase-like ER kinase, phosphorylated c-Jun N-terminal kinase and C/EBP homologous protein. In conclusion, quercetin may have auxiliary therapeutic potential against glucosamine-induced cell apoptosis and inflammation, which may be partially due to alleviation of ER stress. IntroductionDiabetes is a 'coronary heart disease (CHD) equivalent' disease, as epidemiological data has previously demonstrated that patients with diabetes without any prior evidence of CHD are at greater risk of death from CHD than nondiabetic patients with prior evidence of CHD (1,2). Atherosclerosis (AS) is a disease of arterial lipid deposition leading to a number of biological responses, including a chronic, macrophage-dominated inflammatory reaction (3), and is the pathological basis of CHD. The hexosamine biosynthesis pathway (HBP), a normal pathway for glucose metabolism, is activated excessively in patients with diabetes, resulting in increased cellular glucosamine (4). Endoplasmic reticulum (ER) is a membranous network to synthesize, modify, fold and assemble proteins. When the ER function, particularly folding capacity, is challenged, the unfolded protein response (UPR) is executed as a protective mechanism in ER. Failure of this mechanism to fold newly synthesized proteins shows unique damage to the cell and is termed ʻER stressʼ (5,6). Numerous studies have highlighted that ER stress may link hyperglycemia to AS (4,7,8). Important ER stress markers, including protein kinase-like ER kinase (PERK), glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP), were expressed in the arterial wall of streptozotocin-induced hyperglycemic apolipoprotein (apoE)-deficient mice (4). Glucosamine levels and the expression of GRP78 were increased following hyperglycemia and prior to the early stages of fatty streak formation in aortic endothelial cells of hyperglycemic apoE -/-mice (7). In vitro studies have demonstrated that incubation of hepatic cells (9) and adipocytes (10) with 5 mM glucosamine resulted in lipid accumulation, impaired insulin-stimul...

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“…Through further signaling transduction, transcription factor activity is activated to regulate the expression of proteins, ultimately leading to cellular reactions such as cell proliferation, differentiation, conversion, and apoptosis. Experimental studies have shown that in patients with diabetic nephropathy, p38-MAPK activity changed significantly (Wu et al, 2012). In the study by Wu et al (2012), rat glomerular mesangial cells were incubated with different concentrations of glucose as the osmotic pressure control.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental studies have shown that in patients with diabetic nephropathy, p38-MAPK activity changed significantly (Wu et al, 2012). In the study by Wu et al (2012), rat glomerular mesangial cells were incubated with different concentrations of glucose as the osmotic pressure control. High sugar and hypertonic conditions could lead to the decrease in the expression of matrix metalloproteinase 9 (MMP-9) mRNA in rat glomerular mesangial cells, and the increase in mRNA expression of tissue inhibitors of matrix metalloproteinase (TIMP-1).…”

Section: Discussionmentioning

confidence: 99%

Effects of Shenkangling intervention on the MAPK pathway in rats with doxorubicin-induced nephropathy

Yang

Zheng

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Shenkangling plays a role of Yishenhuoxue effect for the treatment of children with nephrotic syndrome. The aim of this study was to investigate the effects of Shenkangling intervention on the mitogen-activated protein kinase (MAPK) pathway in rats with Adriamycin-induced nephropathy (AN) and its underlying mechanism of action. Nephrosis was induced in healthy Sprague-Dawley rats by doxorubicin and the rats were untreated or treated with prednisone, simvastatin, Shenkangling, or a combination thereof. Using real-time PCR, the mRNA expression levels of Chemokine (C-X-C motif) ligand 16 (CXCL16), A Disintegrin and metalloproteinase domain- containing protein 10 (ADAM10), and ADAM17 in the renal tissues of these rats were found to be decreased by the various treatments compared to those in the untreated doxorubicin-induced nephrosis rats. To quantify the activation of the MAPK pathway, western blotting was used to detect the phosphorylation levels of MAPK pathwayassociated proteins (p38, ERK1/2, SAPK/JNK) and nuclear factor (NF)-κB p65, which were reduced by the various treatments compared to those in the untreated doxorubicin-induced rats. Serum levels of transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, quantified by ELISA, were decreased by the various treatments compared to the levels in the untreated doxorubicin-induced nephrosis rats. The rats treated with prednisone, simvastatin, and Shenkangling showed the best outcome. The Chinese medicine Shenkangling that is known for nourishing the kidney and promoting blood circulation reduced urinary protein levels, increased serum albumin levels, and reduced cholesterol levels by reducing the release of CXCL16, ADAM10, ADAM17, TGF-β1, TNF-α, IL-1β, IL-6, and other inflammatory mediators and inhibiting the activation of the MAPK signaling pathway, thereby effectively improving the state of nephropathy in AN rats. These results indicate that Shenkangling can be used clinically to treat nephropathy.

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p38 Mitogen-Activated Protein Kinase Is Required for Glucosamine-Induced Endothelial Nitric Oxide Synthase Uncoupling and Plasminogen-Activator Inhibitor Expression

Cited by 8 publications

References 51 publications

Arginase: The Emerging Therapeutic Target for Vascular Oxidative Stress and Inflammation

Arginase: The Emerging Therapeutic Target for Vascular Oxidative Stress and Inflammation

Quercetin alleviates cell apoptosis and inflammation via the ER stress pathway in vascular endothelial cells cultured in high concentrations of glucosamine

Effects of Shenkangling intervention on the MAPK pathway in rats with doxorubicin-induced nephropathy

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