scholarly journals Folic acid supplementation inhibits NADPH oxidase‐mediated superoxide anion production in the kidney

2011 ◽  
Vol 25 (S1) ◽  
Author(s):  
Sun‐Young Hwang ◽  
Yaw L Siow ◽  
Kathy K.W. Au‐Yeung ◽  
James House ◽  
O Karmin
Keyword(s):  
Folic Acid ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Folic Acid Supplementation ◽  
Superoxide Anion Production ◽  
Acid Supplementation ◽  
Anion Production

Folic acid supplementation inhibits NADPH oxidase-mediated superoxide anion production in the kidney

2011 ◽  
Vol 300 (1) ◽  
pp. F189-F198 ◽  
Author(s):  
Sun-Young Hwang ◽  
Yaw L. Siow ◽  
Kathy K. W. Au-Yeung ◽  
James House ◽  
Karmin O
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Folic Acid ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Folic Acid Supplementation ◽  
Sod Activity ◽  
Superoxide Anion Production ◽  
Acid Supplementation ◽  
Anion Production

Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) levels, is a metabolic disease. It is a common clinical finding in patients with chronic kidney diseases and occurs almost uniformly in patients with end-stage renal disease. Hyperhomocysteinemia is also a risk factor for cardiovascular disease. Our recent studies indicate that hyperhomocysteinemia can lead to renal injury by inducing oxidative stress. Oxidative stress is one of the important mechanisms contributing to Hcy-induced tissue injury. Folic acid supplementation is regarded as a promising approach for prevention and treatment of cardiovascular disease associated with hyperhomocysteinemia due to its Hcy-lowering effect. However, its effect on the kidney is not clear. The aim of this study was to examine the effect of folic acid supplementation on Hcy-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the kidney during hyperhomocysteinemia. Hyperhomocysteinemia was induced in male Sprague-Dawley rats fed a high-methionine diet for 12 wk with or without folic acid supplementation. A group of rats fed a regular diet was used as control. There was a significant increase in levels of superoxide anions and lipid peroxides in kidneys isolated from hyperhomocysteinemic rats. Activation of NADPH oxidase was responsible for hyperhomocysteinemia-induced oxidative stress in the kidney. Folic acid supplementation effectively antagonized hyperhomocysteinemia-induced oxidative stress via its Hcy-lowering and Hcy-independent effect. In vitro study also showed that 5-methyltetrahydrofolate, an active form of folate, effectively reduced Hcy-induced superoxide anion production via NADPH oxidase. Xanthine oxidase activity was increased and superoxide dismutase (SOD) activity was decreased in the kidney of hyperhomocysteinemic rats, which might also contribute to an elevation of superoxide anion level in the kidney. Folic acid supplementation attenuated xanthine oxidase activity and restored SOD activity in the kidney of hyperhomocysteinemic rats. These results suggest that folic acid supplementation may offer renal protective effect against oxidative stress.

Folic acid inhibits homocysteine-induced superoxide anion production and nuclear factor kappa B activation in macrophagesThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigator's Forum.

2006 ◽  
Vol 84 (1) ◽  
pp. 141-147 ◽  
Author(s):  
Kathy K.W. Au-Yeung ◽  
Johnny C.W. Yip ◽  
Yaw L. Siow ◽  
Karmin O
Keyword(s):  
Folic Acid ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Folic Acid Supplementation ◽  
Nuclear Factor ◽  
Superoxide Anion Production ◽  
Monocyte Chemoattractant Protein 1 ◽  
Acid Supplementation

Folic acid supplementation is a promising approach for patients with cardiovascular diseases associated with hyperhomocysteinemia. We have demonstrated that homocysteine (Hcy) activates nuclear factor-κB (NF-κB), a transcription factor that plays an important role in inflammatory responses. The aim of the present study was to investigate the effect of folic acid on Hcy-induced NF-κB activation in macrophages. Hcy treatment (100 μmol/L) resulted in NF-κB activation and increased monocyte chemoattractant protein-1 (MCP-1) expression in THP-1 derived macrophages. Hcy-induced NF-κB activation was associated with a significant increase in the intracellular superoxide anion levels. There was a significant increase in phosphorylation and membrane translocation of NADPH oxidase p47phox subunit in Hcy-treated cells. Addition of folic acid (200 ng/mL) to the culture medium abolished NADPH oxidase-dependent superoxide anion generation in macrophages by preventing phosphorylation of p47phox subunit. Consequently, Hcy-induced NF-κB activation and MCP-1 expression was inhibited. Such an inhibitory effect of folic acid was independent of its Hcy-lowering ability. Taken together, these results suggest that folic acid treatment can effectively inhibit Hcy-induced oxidative stress and inflammatory responses in macrophages. This may represent one of the mechanisms by which folic acid supplementation exerts a protective effect in cardiovascular disorders.

scholarly journals Homocysteine stimulates phosphorylation of NADPH oxidase p47phox and p67phox subunits in monocytes via protein kinase Cβ activation

2006 ◽  
Vol 398 (1) ◽  
pp. 73-82 ◽  
Author(s):  
Yaw L. Siow ◽  
Kathy K. W. Au-Yeung ◽  
Connie W. H. Woo ◽  
Karmin O
Keyword(s):  
Protein Kinase ◽  
Nadph Oxidase ◽  
Superoxide Anion ◽  
Monocytic Cell ◽  
Superoxide Anion Production ◽  
Monocytic Cell Line ◽  
Protein Kinase C Inhibitors ◽  
Human Monocytic Cell Line ◽  
Anion Production ◽  
Human Monocytic Cell

Hyperhomocysteinaemia is an independent risk factor for cardiovascular diseases due to atherosclerosis. The development of atherosclerosis involves reactive oxygen species-induced oxidative stress in vascular cells. Our previous study [Wang and O (2001) Biochem. J. 357, 233–240] demonstrated that Hcy (homocysteine) treatment caused a significant elevation of intracellular superoxide anion, leading to increased expression of chemokine receptor in monocytes. NADPH oxidase is primarily responsible for superoxide anion production in monocytes. In the present study, we investigated the molecular mechanism of Hcy-induced superoxide anion production in monocytes. Hcy treatment (20–100 μM) caused an activation of NADPH oxidase and an increase in the superoxide anion level in monocytes (THP-1, a human monocytic cell line). Transfection of cells with p47phox siRNA (small interfering RNA) abolished Hcy-induced superoxide anion production, indicating the involvement of NADPH oxidase. Hcy treatment resulted in phosphorylation and subsequently membrane translocation of p47phox and p67phox subunits leading to NADPH oxidase activation. Pretreatment of cells with PKC (protein kinase C) inhibitors Ro-32-0432 (bisindolylmaleimide XI hydrochloride) (selective for PKCα, PKCβ and PKCγ) abolished Hcy-induced phosphorylation of p47phox and p67phox subunits in monocytes. Transfection of cells with antisense PKCβ oligonucleotide, but not antisense PKCα oligonucleotide, completely blocked Hcy-induced phosphorylation of p47phox and p67phox subunits as well as superoxide anion production. Pretreatment of cells with LY333531, a PKCβ inhibitor, abolished Hcy-induced superoxide anion production. Taken together, these results indicate that Hcy-stimulated superoxide anion production in monocytes is regulated through PKC-dependent phosphorylation of p47phox and p67phox subunits of NADPH oxidase. Increased superoxide anion production via NADPH oxidase may play an important role in Hcy-induced inflammatory response during atherogenesis.

scholarly journals Role of TSPO/VDAC1 Upregulation and Matrix Metalloproteinase-2 Localization in the Dysfunctional Myocardium of Hyperglycaemic Rats

2020 ◽  
Vol 21 (20) ◽  
pp. 7432 ◽  
Author(s):  
Micaela Gliozzi ◽  
Federica Scarano ◽  
Vincenzo Musolino ◽  
Cristina Carresi ◽  
Miriam Scicchitano ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Nadph Oxidase ◽  
Diabetic Cardiomyopathy ◽  
Superoxide Anion ◽  
Matrix Metalloproteinase 2 ◽  
Superoxide Anion Production ◽  
Anion Production ◽  
Voltage Dependent ◽  
Selective Channel

Clinical management of diabetic cardiomyopathy represents an unmet need owing to insufficient knowledge about the molecular mechanisms underlying the dysfunctional heart. The aim of this work is to better clarify the role of matrix metalloproteinase 2 (MMP-2) isoforms and of translocator protein (TSPO)/voltage-dependent anion-selective channel 1 (VDAC1) modulation in the development of hyperglycaemia-induced myocardial injury. Hyperglycaemia was induced in Sprague-Dawley rats through a streptozocin injection (35 mg/Kg, i.p.). After 60 days, cardiac function was analysed by echocardiography. Nicotinamide Adenine Dinucleotide Phosphate NADPH oxidase and TSPO expression was assessed by immunohistochemistry. MMP-2 activity was detected by zymography. Superoxide anion production was estimated by MitoSOX™ staining. Voltage-dependent anion-selective channel 1 (VDAC-1), B-cell lymphoma 2 (Bcl-2), and cytochrome C expression was assessed by Western blot. Hyperglycaemic rats displayed cardiac dysfunction; this response was characterized by an overexpression of NADPH oxidase, accompanied by an increase of superoxide anion production. Under hyperglycaemia, increased expression of TSPO and VDAC1 was detected. MMP-2 downregulated activity occurred under hyperglycemia and this profile of activation was accompanied by the translocation of intracellular N-terminal truncated isoform of MMP-2 (NT-MMP-2) from mitochondria-associated membrane (MAM) into mitochondria. In the onset of diabetic cardiomyopathy, mitochondrial impairment in cardiomyocytes is characterized by the dysregulation of the different MMP-2 isoforms. This can imply the generation of a “frail” myocardial tissue unable to adapt itself to stress.

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