Redox mechanisms in hepatic chronic wound healing and fibrogenesis.

Under physiological conditions, intracellular and tissue levels of reactive oxygen species (ROS) are carefully controlled and employed as fine modulators of signal transduction, gene expression and cell functional responses (redox signaling). A significant derangement in redox homeostasis, resulting in sustained levels of oxidative stress and related mediators, plays a role in the pathogenesis of human diseases characterized by chronic inflammation, chronic activation of wound healing and tissue fibrogenesis, including chronic liver diseases. In this chapter major concepts and mechanisms in redox signaling will be briefly recalled to introduce a number of selected examples of redox-related mechanisms that can actively contribute to critical events in the natural history of a chronic liver diseases, including induction of cell death, perpetuation of chronic inflammatory responses and fibrogenesis. A major focus will be on redox-dependent mechanisms involved in the modulation of phenotypic responses of activated, myofibroblast-like, hepatic stellate cells (HSC/MFs), still considered as the most relevant pro-fibrogenic cells operating in chronic liver diseases.

Over the past 10 to 15 years, a vast collection of studies have provided evidence indicating that reactive oxygen species (ROS), particularly superoxide (O2·−) and hydrogen peroxide (H2O2), contribute to the pathogenesis of cardiovascular diseases, such as heart failure and hypertension. Griendling et al1 first demonstrated that NADPH oxidase present in the vasculature is a primary source of the elevated ROS levels. Since these initial studies, NADPH oxidase-derived ROS in the kidney,2 heart,3 and brain4 have been linked to the development and progression of numerous cardiovascular-related diseases. More recently, however, mitochondria have also been identified as important sources of ROS in controlling cardiovascular function. Considering that mitochondria are the primary source of ROS in most cells during normal respiration because of the leaking of electrons from the electron transport chain (ETC), perhaps it should not be all that surprising that mitochondrial-produced ROS are involved in pathophysiological conditions of the cardiovascular system. To date, most of the evidence linking mitochondrial dysfunction and mitochondrial-produced ROS to the pathogenesis of cardiovascular diseases comes from studies on the peripheral renin-angiotensin system.5 For example, using a model of cardiac ischemic reperfusion injury, Kimura et al6 reported that angiotensin II (Ang II)-induced preconditioning is mediated by mitochondrial-produced ROS. The authors further demonstrated that Ang II-induced NADPH oxidase-derived ROS lie upstream of mitochondrial-produced ROS, thus, implicating a ROS-induced ROS mechanism. Similarly, it was demonstrated recently that, in aortic endothelial cells, Ang II-induced NADPH oxidase activation leads to an increase in mitochondrial ROS production, as well as mitochondrial dysfunction, as determined by a decrease in mitochondrial membrane potential and mitochondrial respiration.7 Together, these studies and others (detailed elsewhere5) clearly illustrate a role for mitochondrial-produced ROS and mitochondrial dysfunction in peripheral tissues in the pathogenesis of …

Oxidative stress, resulting from increased production of reactive oxygen species (ROS) and/or reduced antioxidant defences, has been implicated in cardiovascular disease pathophysiology for over 2 decades. Based on the concept that this drives both the genesis and progression of conditions such as heart failure, numerous clinical trials of antioxidant therapies were undertaken but were unsuccessful. Nevertheless, experimental data linking oxidative stress and heart disease remain compelling and support continued efforts to develop more effective therapies than antioxidant vitamins.1 In the current issue of Circulation , Zhao et al .2 report that cardiomyocyte-specific high-level overexpression of the ROS-generating enzyme NADPH oxidase-4 (Nox4) aggravated angiotensin II-induced cardiac remodeling and was mitigated by a small molecule Nox inhibitor. The authors propose that Nox4 inhibition may have therapeutic potential to treat cardiac remodeling. Is this proposal reasonable and how should such studies be interpreted within a pathophysiological framework for the roles of ROS in heart failure?

Cellular redox homeostasis is the first line of defense against diverse stimuli and is crucial for various biological processes. Reactive oxygen species (ROS), byproducts of numerous cellular events, may serve in turn as signaling molecules to regulate cellular processes such as proliferation, differentiation, and apoptosis. However, when overproduced ROS fail to be scavenged by the antioxidant system, they may damage cellular components, giving rise to senescent, degenerative, or fatal lesions in cells. Accordingly, this review not only covers general mechanisms of ROS production under different conditions, but also focuses on various types of ROS-involved diseases, including atherosclerosis, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative diseases, and cancer. In addition, potentially therapeutic agents and approaches are reviewed in a relatively comprehensive manner. However, due to the complexity of ROS and their cellular impacts, we believe that the goal to design more effective approaches or agents may require a better understanding of mechanisms of ROS production, particularly their multifaceted impacts in disease at biochemical, molecular, genetic, and epigenetic levels. Thus, it requires additional tools of omics in systems biology to achieve such a goal. Antioxid. Redox Signal. 15, 2867-2908.

The answer: angiotensin II. The question: what do inflammation, oxidant stress and fibrogenesis have in common?

Vascular dysfunction in response to reactive oxygen species (ROS) plays an important role in the development and progression of atherosclerotic lesions. In most cells, mitochondria are the major source of cellular ROS during aerobic respiration. Under most conditions the rates of ROS formation and elimination are balanced through mechanisms that sense relative ROS levels. However, a chronic imbalance in redox homeostasis is believed to contribute to various chronic diseases, including atherosclerosis. Uncoupling protein-2 (UCP2) is a mitochondrial inner membrane protein shown to be a negative regulator of macrophage ROS production. In response to a cholesterol-containing atherogenic diet, C57BL/6J mice significantly increased expression of UCP2 in the aorta, while mice lacking UCP2, in the absence of any other genetic modification, displayed significant endothelial dysfunction following the atherogenic diet. Compared with wild-type mice, Ucp2(-/-) mice had decreased endothelial nitric oxide synthase, an increase in vascular cell adhesion molecule-1 expression, increased ROS production, and an impaired ability to increase total antioxidant capacity. These changes in Ucp2(-/-) mice were associated with increased aortic macrophage infiltration and more numerous and larger atherosclerotic lesions. These data establish that in the vasculature UCP2 functions as an adaptive antioxidant defense to protect against the development of atherosclerosis in response to a fat and cholesterol diet.

UVB Radiation Induces Apoptosis in Keratinocytes by Activating a Pathway Linked to “BLT2-Reactive Oxygen Species”

p47phox contributes to albuminuria and kidney fibrosis in mice

The induction of senescence, an irreversible growth arrest, in cancer cells is regarded as a mean to halt tumor progression. The phytoalexin resveratrol (RV) is known to possess a variety of cancer-preventive, -therapeutic, and -chemosensitizing properties. We report here that chronic treatment with RV in a subapoptotic concentration induces senescence-like growth arrest in tumor cells. In contrast to the widely accepted antioxidant property of RV, we demonstrate that one causative stimulus for senescence induction by chronic RV is an increased level of reactive oxygen species (ROS). The ROS formed upon RV exposure include hydrogen peroxide and superoxide and originate largely from mitochondria. Consistently, co-incubation with the antioxidant N-acetyl cysteine interfered with RV-mediated reactivation of the senescence program. Molecular mediators on the way from increased ROS levels to the observed growth arrest include p38 MAPK, p53, and p21. Moreover, we provide evidence that RV-initiated replication stress, apparent by activation of the ataxia telangiectasia-mutated kinase pathway, is associated with increased ROS levels and senescence induction. This is the first report linking cell cycle effects with a pro-oxidant and pro-senescent effect of RV in cancer cells.

Which Way to Die: the Regulation of Acinar Cell Death in Pancreatitis by Mitochondria, Calcium, and Reactive Oxygen Species

Reactive oxygen species (ROS) produced in the neuronal, renal, and vascular systems not only influence cardiovascular physiology but are also strongly implicated in pathological signaling leading to hypertension. Different sources of ROS have been identified, ranging from xanthine-xanthine oxidase and mitochondria to NADPH oxidase (Nox) enzymes. Of 7 Nox family members, Nox1, Nox2, and Nox4 (and Nox5 in humans) influence the cardiovascular system. Their activation processes and cell and tissue distribution vary widely, adding complexity to understanding their functional roles. Whether these systems act collectively or independently in disease conditions is unclear, but recently feed forward mechanisms have been established between ROS sources. Studies published in Hypertension over the last few years are the focus of this review, and they provide a framework with which to consider the roles of Nox enzymes in neuronal, renal, and vascular hypertensive mechanisms, as well as cardiac remodeling, and their relationships with other ROS-generating systems. ### Neuronal ROS in Hypertension Redox signaling in the central nervous system is well recognized in neuronal control of blood pressure (BP), as well as in response to angiotensin II (Ang II) and aldosterone, which are linked to ROS-dependent hypertension. Recently, new roles for ROS have been described in the hypothalamus and brain stem, nucleus tractus solitarius (NTS), subfornical organ (SFO), rostral ventrolateral medulla, and area postrema (Figure 1). Figure 1. Neuronal NADPH oxidase–dependent ROS involved in central regulation of hypertension. NADPH oxidase homologues, mainly Nox2 and Nox4, are found in different regions of the neuronal system and are reported to have a role in the neuropathogenesis of hypertension by enhancing the sympathetic nerve activity. Nox-induced ROS initiate a forward loop in cross-activation of different receptors and between Nox and mitochondrial ROS. OVLT indicates organum vasculosum of the lamina terminalis; PVN, paraventricular nucleus; PP, posterior pituitary; AP, area postrema; RVLM, rostral ventrolateral medulla. Several …

Reactive oxygen species (ROS) constitute important signaling molecules in the central nervous system. They regulate a number of different functions both under physiological conditions and under pathological conditions. Here we tested the hypothesis that in the immature hippocampus ATP, the most diffuse neurotransmitter in the brain, modulates synaptic transmission via ROS. We show that ATP, acting on metabotropic P2Y1 receptors, increased the frequency of GABA(A)-mediated spontaneous postsynaptic currents (SPSCs) in CA3 principal cells, an effect that was prevented by the antioxidant N-acetyl-cysteine or by catalase, an enzyme that breaks down H2O2. The effect of ATP on SPSCs was mimicked by H2O2 or by the pro-oxidant, Fe2+, which, through the Fentol reaction, catalyzes the conversion of H2O2 into highly reactive hydroxyl radicals. MRS-2179, a P2Y1 receptor antagonist, removed the facilitatory action of Fe2+ on SPSCs, suggesting that endogenous ATP acting on P2Y1 receptors is involved in Fe2+-induced modulation of synaptic transmission. Imaging ROS with the H2O2-sensitive dye DCF revealed that ATP induces generation of peroxide in astrocytes via activation of P2Y1 receptors coupled to intracellular calcium rise. Neither N-acetyl-cysteine nor catalase prevented Ca2+ transients induced by ATP in astrocytes. Since a single hippocampal astrocyte can contact many neurons, ATP-induced ROS signaling may control thousands of synapses. This may be crucial for information processing in the immature brain when GABAergic activity is essential for the proper wiring of the hippocampal network.

In the past several years, a significant body of work has been published in ATVB about new research in the field of vascular biology and redox signaling. We would like to highlight new publications that have enriched our understanding of redox signaling in the context of vasculopathy. Although redox balance and perturbation involve a plethora of proteins and signaling molecules, the focus of recent research has involved the examination of chemically reactive oxygen species (ROS), reactive nitrogen species (RNS), and the interactions with other molecules or enzymes that lead to vascular pathology.1,2 There are often a variety of downstream targets and mechanisms of cross-talk that can lead to pathologies observed in the vasculature as a result of redox imbalance. The objective of this article is to underscore the novel research in the field devoted to vascular redox physiology and disease. The main sources of vascular ROS are NAD(P)H oxidase (NOX),3 mitochondrial-derived superoxide (O2−),4 uncoupled nitric oxide synthase (NOS),5 and to a lesser extent xanthine oxidase,6 cyclooxygenase,7 and myeloperoxidase.8,9 A delicate ROS balance exists within the vascular wall that can be either beneficial or deleterious, depending on the source of ROS or the mechanisms of ROS capture or quenching, and these topics have been extensively discussed in previous reviews.10–12 ROS-associated proteins and their expression profiles vary in depending on vessel location within the vascular tree and tissue origin. Indeed, vascular smooth muscle cells (VSMC), endothelial cells, immune cells, and other hematopoietic cell types have vastly different expression patterns for the various ROS-related proteins. Moreover, these molecules readily change in response to stimuli and disease state.13–19 The balance between NOX protein expression and their role in disease is highly context and tissue …

Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, we reveal the roles of ROS as multifaceted physiological modulators to mediate redox signaling and sustain redox homeostasis. In addition, we also emphasize the detailed OS mechanisms involved in the initiation and development of several important diseases. ROS as a double‐edged sword in disease progression suggest two different therapeutic strategies to treat redox‐relevant diseases, in which targeting ROS sources and redox‐related effectors to manipulate redox homeostasis will largely promote precision medicine. Therefore, a comprehensive understanding of the redox signaling networks under physiological and pathological conditions will facilitate the development of redox medicine and benefit patients with redox‐relevant diseases.

It is well appreciated that reactive oxygen species (ROS) are deleterious to mammals, including humans, especially when generated in abnormally large quantities from cellular metabolism. Whereas the mechanisms leading to the production of ROS are rather well delineated, the mechanisms underlying tissue susceptibility or tolerance to oxidant stress remain elusive. Through an experimental selection over many generations, we have previously generated Drosophila melanogaster flies that tolerate tremendous oxidant stress and have shown that the family of antimicrobial peptides (AMPs) is over-represented in these tolerant flies. Furthermore, we have also demonstrated that overexpression of even one AMP at a time (e.g. Diptericin) allows wild-type flies to survive much better in hyperoxia. In this study, we used a number of experimental approaches to investigate the potential mechanisms underlying hyperoxia tolerance in flies with AMP overexpression. We demonstrate that flies with Diptericin overexpression resist oxidative stress by increasing antioxidant enzyme activities and preventing an increase in ROS levels after hyperoxia. Depleting the GSH pool using buthionine sulfoximine limits fly survival, thus confirming that enhanced survival observed in these flies is related to improved redox homeostasis. We conclude that 1) AMPs play an important role in tolerance to oxidant stress, 2) overexpression of Diptericin changes the cellular redox balance between oxidant and antioxidant, and 3) this change in redox balance plays an important role in survival in hyperoxia.