Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis - PubMed (original) (raw)
Aldose reductase functions as a detoxification system for lipid peroxidation products in vasculitis
H L Rittner et al. J Clin Invest. 1999 Apr.
Abstract
Giant cell arteritis (GCA) is a systemic vasculitis preferentially affecting large and medium-sized arteries. Inflammatory infiltrates in the arterial wall induce luminal occlusion with subsequent ischemia and degradation of the elastic membranes, allowing aneurysm formation. To identify pathways relevant to the disease process, differential display-PCR was used. The enzyme aldose reductase (AR), which is implicated in the regulation of tissue osmolarity, was found to be upregulated in the arteritic lesions. Upregulated AR expression was limited to areas of tissue destruction in inflamed arteries, where it was detected in T cells, macrophages, and smooth muscle cells. The production of AR was highly correlated with the presence of 4-hydroxynonenal (HNE), a toxic aldehyde and downstream product of lipid peroxidation. In vitro exposure of mononuclear cells to HNE was sufficient to induce AR production. The in vivo relationship of AR and HNE was explored by treating human GCA temporal artery-severe combined immunodeficiency (SCID) mouse chimeras with the AR inhibitors Sorbinil and Zopolrestat. Inhibition of AR increased HNE adducts twofold and the number of apoptotic cells in the arterial wall threefold. These data demonstrate that AR has a tissue-protective function by preventing damage from lipid peroxidation. We propose that AR is an oxidative defense mechanism able to neutralize the toxic effects of lipid peroxidation and has a role in limiting the arterial wall injury mediated by reactive oxygen species.
Figures
Figure 1
AR mRNA is upregulated in inflamed temporal arteries. cDNA from temporal arteries of four patients with giant cell arteritis (GCA) and four temporal arteries without histological signs of inflammation were amplified with AR-specific (top) and β-actin–specific primers (bottom). AR-specific sequences could not be detected in normal arteries but were abundantly expressed in inflamed arteries. AR, aldose reductase.
Figure 2
Mononuclear cells and smooth muscle cells in the media express AR. (a) Frozen sections from temporal arteries of patients with GCA and control patients were immunostained with a rabbit polyclonal AR-specific antibody (fluorescent Vector red). Widespread expression of AR in the medial layer was seen in GCA arteries (top). In contrast, AR was virtually absent in unaffected arteries (bottom). Original magnification: ×50. (b) To determine the cell type expressing AR, temporal artery sections were double-stained with a rabbit polyclonal AR-specific antibody (red) and mouse monoclonal antibody against CD3 or CD68 (brown). A fraction of all cell types in the media, including CD3+ T cells (top) and CD68+ macrophages (bottom), expressed AR in areas of prominent tissue destruction. Original magnification: ×1,000.
Figure 3
AR colocalizes with HNE. Adjacent frozen sections from six patients with GCA were labeled with either a rabbit polyclonal antibody against HNE adducts (as a marker for lipid peroxidation) or with an anti-AR antibody. Expression of AR (left) in the media closely correlated with signs of lipid peroxidation and HNE formation (HNE adducts) (right). Original magnification: ×100. HNE, 4-hydroxynonenal.
Figure 4
4-hydroxynonenal (HNE) induces AR in mononuclear cells. PBMCs were stimulated with 5 or 10 μM HNE in serum-free RPMI-1640 for 6 h. Protein (2 μg) was separated on 10% SDS–polyacrylamide gels, and AR was detected by Western blotting. Control samples included a buffer control, 200 μM Sorbinil, and 600 U/ml recombinant human interferon-γ (IFN-γ), respectively. One experiment representative of eight is shown. PBMC, peripheral blood mononuclear cell.
Figure 5
Treatment of temporal artery–SCID mouse chimeras with AR inhibitors increases the lipid peroxidation downstream product HNE. Temporal artery samples from patients were transplanted subcutaneously into SCID mice. Temporal artery–SCID mouse chimeras were injected with either Sorbinil (50 mg/kg/day) or Zopolrestat (50 mg/kg/day) intraperitoneally for 1 week or were sham-treated. The temporal artery grafts were explanted after treatment and stained with antibodies to AR as described in Figure 2. AR expression (red stain) was detected in sections from sham-treated (a) as well as from Sorbinil-treated (b) tissues. Original magnification: ×400. (c) Kidneys were harvested after completion of the treatment, and tissue extracts were adjusted to 0.2 mg protein. HNE in the renal tissue was measured by a lipid peroxidation assay. (d and e) Frozen sections were stained by immunofluorescence with an HNE adduct–specific antibody. The stained area was quantified by laser confocal microscopy, and the percentage of stained tissue in relation to the entire arterial circumference was calculated. SCID, severe combined immunodeficiency.
Figure 6
Treatment of temporal artery–SCID mouse chimeras with AR inhibitors leads to increased apoptosis. Temporal artery tissue from patients with GCA was implanted into SCID mice, and the chimeras were treated with Sorbinil, Zopolrestat, or buffer control as described in Figure 5. Apoptosis in the arterial wall was detected with ISEL staining in tissue sections from grafts explanted from control and Sorbinil- or Zopolrestat-treated SCID mouse chimeras. (a) Apoptotic smooth muscle cells were found in arterial sections of grafts harvested from Sorbinil-treated mice (left) but not in inflamed temporal arteries collected from sham-treated mice (middle) or in tissue sections of noninflamed control arteries explanted from Sorbinil-treated mice (right). (b) The total number of apoptotic cells in the entire arterial circumference was determined. Treatment with Sorbinil (left) as well as Zopolrestat (right) increased the number of apoptotic smooth muscle cells and apoptotic mononuclear cells in comparison to sham-treated controls. ISEL, in situ end labeling.
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