Figure 8.

Mechanistic scheme of adverse cardiovascular effects of noise exposure and protection by HO-1/NRF2 induction or activation. Heme or hemin are involved in the dynamic exchange of Bach1 and Nrf2 in the Maf transcription factor network. Enzymatic degradation of heme is catalyzed by HO-1, leading to the formation of biliverdin, carbon monoxide, and ferrous iron. DMF and its primary intestinal metabolite, monomethyl fumarate (MMF), can bind to the cysteine residues of the NRF2/KEAP-1 complex in the cytoplasm or reduce glutathione (GSH) levels. As a consequence, GSH metabolism may affect the oxidative clearance and increase ROS. Besides Hmox1, NRF2 also regulates other antioxidant and cytoprotective genes encoding for superoxide dismutases, peroxiredoxins, and others. The effects studied in the present study are marked with red color and roman numbers (I,II,III,IV). We found the upregulation of HO-1 and higher plasma levels of bilirubin in response to hemin and DMF treatments (I). Markers of inflammation (IL-6, CD68) and oxidative stress (4-HNE, 3-NT) (II) and aortic, cerebral, and cardiac ROS formation (DHE fluorescence) were suppressed (III), leading to subsequent improvement of blood pressure and endothelial function (ACh response) (IV). Created with BioRender.com.