Aldose Reductase Mediates Mitogenic Signaling in Vascular Smooth Muscle Cells

Ramana, Kota V.; Chandra, Deepak; Srivastava, Sanjay; Bhatnagar, Aruni; Aggarwal, Bharat B.

doi:10.1074/jbc.m202126200

Cited by 92 publications

(152 citation statements)

References 41 publications

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“…Therefore, we tested the hypothesis that GS-DHN, the product of AR-catalyzed reduction of the glutathione conjugate of HNE, is the active metabolite that mediates HNE signaling and mitogenesis. This view is consistent with our previous observations that inhibition of AR (AKR1B4) prevents protein kinase C activation and NF-B activation (43)(44)(45) and inhibits VSMC growth (37,43). Our current results demonstrate the selective ability of GS-DHN in mediating HNE-induced VSMC growth and support the view that AR-catalyzed reduction of glutathione conjugates in general may be a critical and essential interface between detoxification and signaling.…”

supporting

confidence: 93%

“…Antisense Ablation of AR-Antisense ablation of AR (AKR1B4) was carried out as described (43). Briefly, VSMC were transfected with 1 M AR antisense and mismatch control oligonucleotides in Opti-MEM for 12 h using Lipofectamine Plus (15 g/ml) as a transfection reagent as described by the supplier's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…Electrophoretic Mobility Gel Shift Assays-Cytosolic and nuclear extracts were prepared as described (43). Consensus oligonucleotides for NF-B and AP-1 transcription factors were 5Ј-end labeled using T4 polynucleotide kinase.…”

Section: Methodsmentioning

confidence: 99%

“…Consensus oligonucleotides for NF-B and AP-1 transcription factors were 5Ј-end labeled using T4 polynucleotide kinase. The assay procedure was as described before (43). Briefly, nuclear extracts prepared from various control and treated cells were incubated with the labeled oligonucleotides for NF-B or AP-1 for 15 min at 37°C, and the DNA-protein complex formed was resolved on 6.5% native polyacrylamide gels.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous studies show that inhibition of AR abolishes PKC activation as well as NF-B-and AP-1-dependent gene transcription (43)(44)(45)47). Therefore, we examined the effect of HNE, GS-HNE, and GS-DHN on the activation of NF-B, AP-1, and PKC in VSMC in the absence and the presence of the AR inhibitor, tolrestat (10 M).…”

Section: Activation Of Pkc and Nf-b By Hne And Itsmentioning

confidence: 98%

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Mitogenic Responses of Vascular Smooth Muscle Cells to Lipid Peroxidation-derived Aldehyde 4-Hydroxy-trans-2-nonenal (HNE)

Ramana

Bhatnagar

Srivastava

et al. 2006

Journal of Biological Chemistry

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131

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Products of lipid peroxidation such as 4-hydroxy-trans-2-nonenal (HNE) trigger multiple signaling cascades that variably affect cell growth, differentiation, and apoptosis. Because glutathiolation is a significant metabolic fate of these aldehydes, we tested the possibility that the bioactivity of HNE depends upon its conjugation with glutathione. Addition of HNE or the cell-permeable esters of glutathionyl-4-hydroxynonenal (GS-HNE) or glutathionyl-1,4-dihydroxynonene (GS-DHN) to cultures of rat aortic smooth muscle cells stimulated protein kinase C, NF-B, and AP-1, and increased cell growth. The mitogenic effects of HNE, but not GS-HNE or GS-DHN, were abolished by glutathione depletion. Pharmacological inhibition or antisense ablation of aldose reductase (which catalyzes the reduction of GS-HNE to GS-DHN) prevented protein kinase C, NF-B, and AP-1 stimulation and the increase in cell growth caused by HNE and GS-HNE, but not GS-DHN. The growth stimulating effect of GS-DHN was enhanced in cells treated with antibodies directed against the glutathione conjugate transporters RLIP76 (Ral-binding protein) or the multidrug resistance protein-2. Overexpression of RLIP76 abolished the mitogenic effects of HNE and its glutathione conjugates, whereas ablation of RLIP76 using RNA interference promoted the mitogenic effects. Collectively, our findings suggest that the mitogenic effects of HNE are mediated by its glutathione conjugate, which has to be reduced by aldose reductase to stimulate cell growth. These results raise the possibility that the glutathione conjugates of lipid peroxidation products are novel mediators of cell signaling and growth.Incomplete reduction of oxygen leads to the generation of highly reactive species. When generated in high concentrations, the reactive oxygen species (ROS) 2 cause tissue injury and cell death. Excessive ROS production has been linked to a number of degenerative diseases including atherosclerosis (1-3), Alzheimer disease (4, 5), and heart failure (6 -8), as well as tissue injury and dysfunction associated with myocardial ischemia and reperfusion (9, 10) and diabetes (11,12). Additionally, recent evidence suggests that ROS are physiological regulators and mediators of cell signaling due to cytokines and growth factors (13-16). Under physiological conditions, the biological effects of ROS are tightly regulated by chemical and enzymatic antioxidant defenses. However, when these defenses are overwhelmed by disease or injury, ROS attack many cell constituents, with unsaturated lipids being the main target. Unsaturated lipids provide a readily extractable proton to oxygen-free radicals. The resultant lipid radical is stabilized by the bis-allylic double bond system and rapidly accepts molecular oxygen to form peroxyl radicals. This initiates a series of complex, autocatalytic reactions that generate a variety of carbonyl compounds as their end products (17). Of these, aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE) are the most abundant and hence of greater biological significance (...

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supporting

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Activation Of Pkc and Nf-b By Hne And Itsmentioning

confidence: 98%

See 3 more Smart Citations

Mitogenic Responses of Vascular Smooth Muscle Cells to Lipid Peroxidation-derived Aldehyde 4-Hydroxy-trans-2-nonenal (HNE)

Ramana

Bhatnagar

Srivastava

et al. 2006

Journal of Biological Chemistry

Self Cite

131

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C‐terminal lysine processing of human immunoglobulin G2 heavy chain in vivo

Cai

Pan

Flynn

2010

Biotech & Bioengineering

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Although human IgG heavy chain genes encode a C-terminal lysine, this residue is mostly absent from the endogenous antibodies isolated from serum. Some low but variable level of C-terminal lysine is present on therapeutic antibodies expressed in mammalian cell culture systems. Here, we monitored the C-terminal lysine processing of a recombinant human IgG2 antibody after intravenous injection into human subjects. Peptide mapping of the therapeutic antibody isolated from serum samples by affinity purification was used to quantify the C-terminal lysine levels over time in vivo. The C-terminal lysine residue was found to be rapidly lost in vivo with a half life of about an hour (62 min). In vivo C-terminal lysine processing could be reproduced in vitro, but at a faster rate, by incubating in human serum. Pretreated serum, under conditions used to inactivate carboxypeptidase U, generated in vitro C-terminal lysine processing rates that more closely matched those in vivo. Endogenous IgG, isolated from human blood, contained very low levels of C-terminal lysine (∼0.02%), consistent with the expected circulating half life of antibodies and the calculated C-terminal lysine processing rate. Thus, the low residual IgG2 C-terminal lysine is rapidly processed in vivo and such processing likely occurs on endogenous antibodies in circulation.

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Aldo–keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: Implication for cancer intervention

Yan

et al. 2007

Intl Journal of Cancer

125

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Aldo-keto reductase family 1 B10 (AKR1B10), a member of aldoketo reductase superfamily, is overexpressed in human hepatocellular carcinoma, lung squamous cell carcinoma and lung adenocarcinoma. Our previous study had demonstrated that the ectopic expression of AKR1B10 in 293T cells promotes cell proliferation. To evaluate its potential as a target for cancer intervention, in the current study we knocked down AKR1B10 expression in HCT-8 cells derived from a colorectal carcinoma, using chemically synthesized small interfering RNA (siRNA). The siRNA 1, targeted to encoding region, downregulated AKR1B10 expression by more than 60%, and siRNA 2, targeted to 3 0 untranslational region, reduced AKR1B10 expression by more than 95%. AKR1B10 silencing resulted in approximately a 50% decrease in cell growth rate and nearly 40% suppression of DNA synthesis. More importantly, AKR1B10 downregulation significantly reduced focus formation rate and colony size in semisolid culture, indicating the critical role of AKR1B10 in HCT-8 cell proliferation. Recombinant AKR1B10 protein showed strong enzymatic activity to acrolein and crotonaldehyde, with K m 5 110.1 6 12.2 lM and V max 5 3,122.0 6 64.7 nmol/mg protein/min for acrolein and K m 5 86.7 6 14.3 lM and V max 5 2,647.5 6 132.2 nmol/mg protein/min for crotonaldehyde. AKR1B10 downregulation enhanced the susceptibility of HCT-8 cells to acrolein (25 lM) and crotonaldehyde (50 lM), resulting in rapid oncotic cell death characterized with lactate dehydrogenase efflux and annexin-V staining. These results suggest that AKR1B10 may regulate cell proliferation and cellular response to additional carbonyl stress, thus being a potential target for cancer intervention. ' 2007 Wiley-Liss, Inc.Key words: aldose reductase-like-1; aldo-keto reductase family 1 B10; reactive carbonyls; gene silencing; clonogenic growth Aldo-keto reductase family 1 B10 (AKR1B10, also designated aldose reductase-like-1, ARL-1) is a novel member of aldo-keto reductase (AKR) superfamily, isolated from human hepatocellular carcinoma (HCC). 1 The AKR superfamily is involved in intracellular detoxification, carcinogenesis and cancer therapeutics. 2,3 Enhanced expression of aldose reductase (AR, also referred to as AKR1B1) is recognized in many types of tumors. 1,4,5 Inhibition of AR activity results in cancer cell growth inhibition and susceptibility to carbonyl compounds and chemotherapeutic agents, 6,7 while induction of AR expression leads to tumor cell resistance to anticancer drugs. 8 Therefore, AR inhibitors developed for the treatment of diabetic complications have become potential chemotherapeutic agents for cancers with AR overexpression. 7,9 AR also regulates mitogenic signaling pathways in vascular smooth muscle cells and vascular endothelial cells, controlling cells growth. 10,11 AKR1B10 shows 71% amino acid sequence identity to AR. 1 Unlike the ubiquitous expression of AR, the AKR1B10 gene is primarily expressed in the small intestine and colon, with lower levels in the liver, thymus, prostate and testes. ...

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Aldose Reductase Mediates Mitogenic Signaling in Vascular Smooth Muscle Cells

Cited by 92 publications

References 41 publications

Mitogenic Responses of Vascular Smooth Muscle Cells to Lipid Peroxidation-derived Aldehyde 4-Hydroxy-trans-2-nonenal (HNE)

Mitogenic Responses of Vascular Smooth Muscle Cells to Lipid Peroxidation-derived Aldehyde 4-Hydroxy-trans-2-nonenal (HNE)

C‐terminal lysine processing of human immunoglobulin G2 heavy chain in vivo

Aldo–keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: Implication for cancer intervention

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