Cardiac and renal upregulation of Nox2 and NF-κB and repression of Nox4 and Nrf2 in season- and diabetes-mediated models of vascular oxidative stress in guinea-pig and rat.

Anna Gajos-Draus,Monika Duda,Andrzej Beręsewicz

doi:10.14814/phy2.13474

Anna Gajos-Draus, Monika Duda + Show 1 more

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https://doi.org/10.14814/phy2.13474

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Abstract

The superoxide‐forming NADPH oxidase homologues, Nox1, Nox2, and Nox5, seem to mediate the pro‐atherosclerotic vascular phenotype. The hydrogen peroxide‐forming Nox4 afforded vascular protection, likely via NF‐E2‐related factor‐2 (Nrf2) activation and/or Nox2 downregulation in transgenic mice. We hypothesized that oxidative stress in the intact vasculature involves, aside from the upregulation of the superoxide‐forming Noxs, the downregulation of the Nox4/Nrf2 pathway. Guinea‐pigs and rats were studied either in winter or in summer, and the streptozotocin diabetic rats in winter. Plasma nitrite, and superoxide production by isolated hearts were measured, while frozen tissues served in biochemical analyses. Summer in both species and diabetes in rats downregulated myocardial Nox4 while reciprocally upregulating Nox2 and Nox5 in guinea‐pigs, and Nox2 in rats. Simultaneously, myocardial Nrf2 activity and the expression of the Nrf2‐directed heme oxygenase‐1 and endothelial NO synthase were reduced while activity of the nuclear factor κB (NF‐κB) and the expression of NF‐κB‐directed inducible NO synthase and the vascular cell adhesion molecule‐1 were increased. Cardiac superoxide production was increased while plasma nitrite was decreased reciprocally. Analogous disregulation of Noxs, Nrf2, and NF‐κB, occurred in diabetic rat kidneys. Given the diversity of the experimental settings and the uniform pattern of the responses, we speculate that: (1) chronic vascular oxidative stress is a nonspecific (model‐, species‐, organ‐independent) response involving the induction of Nox2 (and Nox5 in guinea‐pigs) and the NF‐κB pathway, and the repression of Nox4 and the Nrf2 pathway; and (2) the systems Nox2‐NF‐κB and Nox4‐Nrf2 regulate each other negatively.

Highlights

Vascular oxidative stress, characterized by excess vascular production of reactive oxygen species (ROS), endothelial dysfunction, and atheroprone vascular phenotype, and arising from dysregulated redox-signaling, is a common feature of multiple forms of cardiovascular disease (CVD), including atherosclerosis and diabetic vasculopathies
We have evaluated cardiac Nox1, Nox2, Nox4, and Nox5 protein expression, and its correlations with: (1) cardiac O2À generation and plasma nitrite concentration used as markers of oxidative stress and endothelial dysfunction, respectively; (2) myocardial activity of nuclear factor jB (NF-jB) and NF-E2related factor-2 (Nrf2), and (iii) myocardial expression of several proteins directed by NF-jB and Nrf2
In line with findings from our earlier work (Konior et al 2011), guinea-pig and rat hearts studied in the summer versus in the winter were found to be characterized by significantly increased O2À generation (Fig 1A), and increased enzymatic NADPH oxidase (Nox) activity (Fig. 1B)

Summary

Introduction

Vascular oxidative stress, characterized by excess vascular production of reactive oxygen species (ROS), endothelial dysfunction, and atheroprone vascular phenotype, and arising from dysregulated redox-signaling, is a common feature of multiple forms of cardiovascular disease (CVD), including atherosclerosis and diabetic vasculopathies. Cardiovascular risk factors mediate the production of excess vascular superoxide (O2À). Transcriptional alterations by these ROS and/or reactive nitrogen species (RNS) mediate atherogenic vascular inflammation and remodelling. In line with this scenario: (1) endothelial dysfunction, and its biochemical marker plasma nitrite level (Kleinbongard et al 2003), correlate with the classical cardiovascular risk-factor profile a 2017 The Authors.

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