Noise-Induced Vascular Dysfunction, Oxidative Stress, and Inflammation Are Improved by Pharmacological Modulation of the NRF2/HO-1 Axis

Abstract

Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. In our previous studies, we investigated the influence of aircraft noise exposure on molecular mechanisms, identifying oxidative stress and inflammation as central players in mediating vascular function. The present study investigates the role of heme oxygenase-1 (HO-1) as an antioxidant response preventing vascular consequences following exposure to aircraft noise. C57BL/6J mice were treated with the HO-1 inducer hemin (25 mg/kg i.p.) or the NRF2 activator dimethyl fumarate (DMF, 20 mg/kg p.o.). During therapy, the animals were exposed to noise at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A). Our data showed a marked protective effect of both treatments on animals exposed to noise for 4 days by normalization of arterial hypertension and vascular dysfunction in the noise-exposed groups. We observed a partial normalization of noise-triggered oxidative stress and inflammation by hemin and DMF therapy, which was associated with HO-1 induction. The present study identifies possible new targets for the mitigation of the adverse health effects caused by environmental noise exposure. Since natural dietary constituents can achieve HO-1 and NRF2 induction, these pathways represent promising targets for preventive measures.

Long-Term Effects of Aircraft Noise Exposure on Vascular Oxidative Stress, Endothelial Function and Blood Pressure: No Evidence for Adaptation or Tolerance Development

“…The lack of further deterioration of endothelial function may indicate that there is a mitigating mechanism ("rescue" pathway) that prevents the observed further increases in oxidative stress within the vasculature being translated into a further deterioration of vascular function. We have previously reported that transcription factor Nrf2 may represent an important defense system for preventing the cardiovascular effects noise and that the expression of a down-stream target of Nrf2, heme oxygenase 1, is also induced by noise exposure while concentrations of its antioxidant product bilirubin are diminished (Jimenez et al, 2021). Therefore, it seems likely that an additional antioxidant mechanism may exist that mitigates further exacerbation of a stressed phenotype.…”

Redox Switches in Noise-Induced Cardiovascular and Neuronal Dysregulation

“…Hahad et al, 2021a;Osborne et al, 2021). Noisemediated inflammation in mice was also prevented by genetic Nox2 deletion as shown by two independent preclinical studies (Kroller-Schon et al, 2018;Eckrich et al, 2021) and antioxidant pharmacological activation/induction of the Nrf2-HO1-axis (Bayo Jimenez et al, 2021).…”

“…This is probably the reason, aside from stress hormone-dependent activation and infiltration of immune cells into the vasculature, for the observed noise-triggered inflammation in exposed mice ( Munzel et al, 2017 ; Kroller-Schon et al, 2018 ; Steven et al, 2020 ; Eckrich et al, 2021 ; Frenis et al, 2021 ) but also the shift to a pro-atherothrombotic phenotype of the plasma proteome of train noise-exposed healthy human subjects ( Herzog et al, 2019 ), epigenetic changes that promote immune cell activation and expression of CRP ( Cai et al, 2017 ; Eze et al, 2020 ) and amygdala activation driven coronary atherosclerosis ( Osborne et al, 2020 ; Hahad et al, 2021a ; Osborne et al, 2021 ). Noise-mediated inflammation in mice was also prevented by genetic Nox2 deletion as shown by two independent preclinical studies ( Kroller-Schon et al, 2018 ; Eckrich et al, 2021 ) and antioxidant pharmacological activation/induction of the Nrf2-HO1-axis ( Bayo Jimenez et al, 2021 ).…”

“…Our model also finds increases in leukocyte infiltration into the aortic endothelium, causing endothelial dysfunction ( Kroller-Schon et al, 2018 ) that appears to be phagocytic NADPH oxidase (Nox2) ( Kroller-Schon et al, 2018 ) and macrophage/monocyte-dependent ( Frenis et al, 2021 ). These effects can be prevented by induction of the antioxidant principle nuclear factor E2 related factor-2 (Nrf2)/heme oxygenase 1 (HO-1) axis ( Bayo Jimenez et al, 2021 ), implying a critical link between oxidative stress and the onset of adverse cardiovascular effects of noise. This postulate is also supported by numerous oxidative stress markers found in noise-exposed animals such as 3-nitrotyrosine-, malondialdehyde- or 4-hydroxynonenal-positive proteins in different tissues and plasma/serum as well as S-glutathionylated endothelial nitric oxide synthase (eNOS) and uncoupled neuronal nitric oxide synthase (nNOS) and directly measured reactive oxygen species (ROS) formation by high performance liquid chromatography (HPLC)-based quantification of 2-hydroxyethidium and various other staining techniques or oxidative burst ( Munzel et al, 2017 ; Kroller-Schon et al, 2018 ; Kvandova et al, 2020 ; Steven et al, 2020 ; Frenis et al, 2021 ).…”

Hemin with Peroxidase Activity Can Inhibit the Oxidative Damage Induced by Ultraviolet A

“…On the other hand, nuclear factor erythroid-2-related factor 2 (Nrf2) is responsible for the cellular response to oxidative stress. When it is activated by hemin, the expression of antioxidant enzymes in cells increases, and those can attenuate the oxidative stress caused by GOX or ultraviolet rays [ 30 , 31 , 32 ].…”