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Altered Nitric Oxide Signaling and Oxidative Stress Increase Pulmonary Arteriolar Tone and Cause Lung Fibrosis in a Mouse Model of Alzheimer's Disease
Author(s) -
Roberts Andrew M,
Jagadapillai Rekha,
Vaishnav Radhika,
Friedland Robert P.,
Drinovac Robert,
Lin Xingyu,
Gozal Evelyne
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.960.3
Subject(s) - oxidative stress , nitric oxide synthase , nitric oxide , endothelial dysfunction , lung , medicine , endocrinology , endothelial nos , pulmonary fibrosis , hypoxic pulmonary vasoconstriction , pathology , enos
Vascular dysfunction and decreased cerebral blood flow in aging have been linked to Alzheimer's Disease (AD). A common feature of aging and cerebrovascular disease is decreased endothelial nitric oxide (NO). Existing evidence suggests that the loss of NO in human cerebrovascular endothelium and increased reactive nitrogen species increase expression of APP and production of Aβ peptides, supporting the concept that a loss of endothelial NO might significantly contribute to the initiation and progression of AD pathology. However, the decrease of systemic NO bioavailability in AD patients is not well characterized and, when occurring in the lung, the resulting endothelial dysfunction may impact pulmonary microcirculation. We hypothesized that systemic NO decrease in AD may induce pulmonary endothelial dysfunction, impairing vascular responses, and result in lung injury. The acute effect of NO synthase (NOS) inhibition on pulmonary arteriolar tone was assessed in anesthetized, male transgenic mice (TgAD; 15–29 months old) expressing the human amyloid beta precursor protein APP gene, 770 isoform with the Swedish, Dutch and Iowa mutations (C57BL/6‐Tg(Thy‐1APP (SwDut Iowa) Bwevn/J mice) and age‐matched wild type controls (C57BL/6J). Pulmonary arteriolar diameters (ranging from 22 to 54 μm) were measured before and after administration of the nitric oxide synthase (NOS) inhibitor, L‐NAME (0.1mg/g body wt). Lung superoxide formation (DHE) and lipid peroxidation (4‐HNE) were assessed as indicators of oxidative stress, and type I and type III collagen deposition (Sirius Red) was used as a marker of pulmonary fibrosis. Inducible NOS (iNOS) expression was determined by Western blotting and immunohistochemistry. In WT mice, administration of L‐NAME caused constriction of pulmonary arterioles (13.6 ± 8.6%, mean ± SD, p<0.05, n = 4). In contrast, L‐NAME administration caused significant dilation of pulmonary arterioles in TgAD mice (14.7 ± 6.2%, p<0.05, n = 6). DHE, 4‐HNE, Sirius Red and iNOS staining increased in TgAD lung tissue samples, compared to WT mice. These data suggest that increased pulmonary arteriolar tone in WT mice may result from a loss of the vasodilator influence of bioavailable NO. However, although bioavailable NO may be decreased in TgAD mice, inhibition of NOS with L‐NAME appears to have a vasodilator effect by decreasing formation of reactive oxygen species. We conclude that increased pulmonary microvascular tone may occur in AD as a result of loss of bioavailable NO and increased oxidative stress.