Responses to reductive stress in the cardiovascular system

Abstract

There is a growing appreciation that reductive stress represents a disturbance in the redox state that is harmful to biological systems. On a cellular level, the presence of increased reducing equivalents and the lack of beneficial fluxes of reactive oxygen species can prevent growth factor-mediated signalling, promote mitochondrial dysfunction, increase apoptosis, and decrease cell survival. In this review, we highlight the importance of redox balance in maintaining cardiovascular homeostasis and consider the tenuous balance between oxidative and reductive stress. We explain the role of reductive stress in models of protein aggregation-induced cardiomyopathies, such as those caused by mutations in αB-crystallin. In addition, we discuss the role of NADPH oxidases in models of heart failure and ischemia-reperfusion to illustrate how oxidants may mediate the adaptive responses to injury. NADPH oxidase 4, a hydrogen peroxide generator, also has a major role in promoting vascular homeostasis through its regulation of vascular tone, angiogenic responses, and effects on atherogenesis. In contrast, the lack of antioxidant enzymes that reduce hydrogen peroxide, such as glutathione peroxidase 1, promotes vascular remodeling and is deleterious to endothelial function. Thus, we consider the role of oxidants as necessary signals to promote adaptive responses, such as the activation of Nrf2 and eNOS, and the stabilization of Hif1. In addition, we discuss the adaptive metabolic reprogramming in hypoxia that lead to a reductive state, and the subsequent cellular redistribution of reducing equivalents from NADH to other metabolites. Finally, we discuss the paradoxical ability of excess reducing equivalents to stimulate oxidative stress and promote injury.

Photodynamic therapy using talaporfin sodium induces heme oxygenase-1 expression in rat malignant meningioma KMY-J cells

“…1C), it indicated that the expression of HO-1 (encoded by Hmox1) is induced by TS-PDT before the appearance of its cytotoxic effect. It is known that the expression of HO-1 is regulated by not only Nrf2-ARE pathway but also hypoxia-inducible factor 1 (HIF-1)-Hypoxia Response Element (HRE) pathway (Handy and Loscalzo, 2017). Because the increased expression of Nqo1, Gpx1, and Gstp1, which are downstream target genes of Nrf2-ARE pathway (Taguchi and Yamamoto, 2017), was not observed by TS-PDT treatment at an early time point, it is possible that the expression of HO-1 may be regulated by HIF-1-HRE pathway.…”

Nitric oxide maintains endothelial redox homeostasis through PKM 2 inhibition

“…The activity of the GSH reductase regenerates GSH from GSSG using NADPH as an electron donor; for reviews, see Ref. (Diaz‐Vivancos et al , ; Handy & Loscalzo, ), but endothelial cell activation can increase the generation of reactive oxygen species to the extent that the reductase cannot compensate for the oxidation of GSH. The resulting oxidative stress has numerous consequences for cell function and is linked with the scavenging of NO, to generate the more potent oxidant peroxynitrite and promote the development of cardiovascular diseases (Forstermann et al , ).…”

Mesencephalic astrocyte–derived neurotrophic factor is an ER-resident chaperone that protects against reductive stress in the heart

“…While ROS generated during I/R can result in protein misfolding, protein misfolding can also be caused by impaired disulfide bond formation. Disulfide bonds, formed in nascent ER proteins, are dependent on the presence of oxygen and the optimal redox environment of the ER, which is likely to shift toward a reductive environment during reperfusion, as the ER redox machinery needs time to recover during oxygen reintroduction, much like how mitochondria need time to recover 6,[21][22][23][24][25][26][27][28][29] . Accordingly, we assessed whether MANF is protective during reductive stress by treating NRVM with the reducing agent, DTT.…”

“…To determine how MANF could maintain ER protein-folding during reperfusion injury we pharmacologically mimicked non-reductive and reductive ER stress using TG or TM and DTT respectively 23,25,27,30,57 . We observed that MANF was required for myocyte viability during reductive ER stress, but it was dispensable during nonreductive ER stress.…”