Nrf2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress (original) (raw)
Related papers
Cells
Reactive oxygen species (ROS) induce nuclear factor erythroid 2–related factor 2 (Nrf2) activation as an adaptive defense mechanism, determining the synthesis of antioxidant molecules, including heme-oxygenase-1 (HO-1). HO-1 protects cells against oxidative injury, degrading free heme and inhibiting ROS production. HO-1 is highly expressed in macrophages during plaque growth. Macrophages are morpho-functionally heterogeneous, and the prevalence of a specific phenotype may influence the plaque fate. This heterogeneity has also been observed in monocyte-derived macrophages (MDMs), a model of macrophages infiltrating tissue. The study aims to assess oxidative stress status and Nrf2/HO-1 axis in MDM morphotypes obtained from healthy subjects and coronary artery disease (CAD) patients, in relation to coronary plaque features evaluated in vivo by optical coherence tomography (OCT). We found that MDMs of healthy subjects exhibited a lower oxidative stress status, lower Nrf2 and HO-1 levels...
European Journal of Pharmacology, 2011
Although heme oxygenase-1 (HO-1) has been implicated in protection against atherogenesis, its role in vulnerable plaques remains to be fully elucidated. This study was aimed to explore the effect of HO-1 on the progression and stabilization of vulnerable plaques and the possible mechanism. We established a vulnerable plaque model by local transfection with recombinant p53 adenovirus to plaques in rabbits fed a high-cholesterol diet. HO-1 activity was modulated by intraperitoneal injection of hemin or Sn-protoporphyrin IX (SnPP). HO-1 induction by hemin inhibited the progression of atherosclerotic lesions and changed the plaque morphology and composition into a more stable phenotype. In addition, hemin treatment is associated with a reduction in matrix metalloproteinase-9, interleukin-6 and tumor necrosis factor-α production, an increase in interleukin-10 level, as well as a decrease of TUNEL labeled apoptosis of smooth muscle cells in lesions. Compared with the control group, aortic nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) activity decreased markedly, whereas endothelial nitric oxide synthase (eNOS) activity increased significantly in the Hemin group. In contrast, inhibition of HO-1 by SnPP induced reversed effects and augmented plaque progression and vulnerability. After pharmacological triggering, the incidence of plaque disruption in SnPP group was significantly higher than that in control group (79% vs. 33%, P b 0.05), while no plaque in Hemin group developed disruption (0% vs. 33%, P b 0.05). These findings suggest that HO-1 induction could delay progression and enhance stability of atherosclerotic plaques, possibly through the attenuation of plaque inflammation and apoptosis, and the suppression of iNOS/NO production.
Heme Oxygenase1 Expression in Macrophages Plays a Beneficial Role in Atherosclerosis
2010
Heme oxygenase (HO-1) is the rate-limiting enzyme in the catabolism of heme, which leads to the generation of biliverdin, iron, and carbon monoxide. It has been shown to have important antioxidant and antiinflammatory properties that result in a vascular antiatherogenic effect. To determine whether HO-1 expression in macrophages constitutes a significant component of the protective role in atherosclerosis, we evaluated the effect of decreased or absent HO-1 expression in peritoneal macrophages on oxidative stress and inflammation in vitro, and the effect of complete deficiency of HO-1 expression in macrophages in atherosclerotic lesion formation in vivo. We found that compared with HO-1 ϩ/ϩ controls, peritoneal macrophages from HO-1 Ϫ/Ϫ and HO-1 ϩ/Ϫ mice exhibited (1) increased reactive oxygen species (ROS) generation, (2) increased proinflammatory cytokines such as monocyte chemotactic protein 1 (MCP-1) and interleukin 6 (IL-6), and (3) increased foam cell formation when treated with oxLDL, attributable in part to increased expression of scavenger receptor A (SR-A). Bone marrow transplantation experiments performed in lethally irradiated LDL-R null female mice, reconstituted with bone marrow from HO-1 Ϫ/Ϫ versus HO-1 ϩ/ϩ mice, revealed that HO-1 Ϫ/Ϫ reconstituted animals exhibited atherosclerotic lesions with a greater macrophage content as evaluated by immunohistochemistry and planimetric assessment. We conclude that HO-1 expression in macrophages constitutes an important component of the antiatherogenic effect by increasing antioxidant protection and decreasing the inflammatory component of atherosclerotic lesions.
Heme Oxygenase and Atherosclerosis
Arteriosclerosis, Thrombosis, and Vascular Biology, 2005
Overproduction of reactive oxygen species under pathophysiological conditions, including dyslipidemia, hypertension, diabetes, and smoking, is integral in the development of cardiovascular diseases (CVD). The reactive oxygen species released from all types of vascular cells regulate various signaling pathways that mediate not only vascular inflammation in atherogenesis but also antioxidative and antiinflammatory responses. One such protective and stress-induced protein is heme oxygenase (HO). HO is the first rate-limiting enzyme in heme breakdown to generate equimolar quantities of carbon monoxide, biliverdin, and free ferrous iron. Accumulating evidence has shown that inducible HO (HO-1) and its products function as adaptive molecules against oxidative insults. The proposed mechanisms by which HO-1 exerts its cytoprotective effects include its abilities to degrade the pro-oxidative heme, to release biliverdin and subsequently convert it bilirubin, both of which have antioxidant pro...
Heme Oxygenase 1 Determines Atherosclerotic Lesion Progression Into a Vulnerable Plaque
Circulation, 2009
Background-The molecular regulation for the transition from stable to vulnerable plaque remains to be elucidated. Heme oxygenase 1 (HO-1) and its metabolites have been implicated in the cytoprotective defense against oxidative injury in atherogenesis. In this study, we sought to assess the role of HO-1 in the progression toward plaque instability in carotid artery disease in patients and in a murine model of vulnerable plaque development. Methods and Results-Atherectomy biopsy from 112 patients with clinical carotid artery disease was collected and stratified according to characteristics of plaque vulnerability. HO-1 expression correlated closely with features of vulnerable human atheromatous plaque (PϽ0.005), including macrophage and lipid accumulation, and was inversely correlated with intraplaque vascular smooth muscle cells and collagen deposition. HO-1 expression levels correlated with the plaque destabilizing factors matrix metalloproteinase-9, interleukin-8, and interleukin-6. Likewise, in a vulnerable plaque model using apolipoprotein E Ϫ/Ϫ mice, HO-1 expression was upregulated in vulnerable versus stable lesions. HO-1 induction by cobalt protoporphyrin impeded lesion progression into vulnerable plaques, indicated by a reduction in necrotic core size and intraplaque lipid accumulation, whereas cap thickness and vascular smooth muscle cells were increased. In contrast, inhibition of HO-1 by zinc protoporphyrin augmented plaque vulnerability. Plaque stabilizing was prominent after adenoviral transduction of HO-1 compared with sham virus-treated animals, providing proof that the observed effects on plaque vulnerability were HO-1 specific. Conclusions-Here we demonstrate in a well-defined patient group and a murine vulnerable plaque model that HO-1 induction reverses plaque progression from a vulnerable plaque to a more stable phenotype as part of a compensatory atheroprotective response. (Circulation. 2009;119:3017-3027.) (V.J., M.P.S.). *The first 2 authors contributed equally to this work. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.808618/DC1.
Journal of Experimental Medicine, 2006
Oxidative stress is implicated in atherogenesis, yet most clinical trials with antioxidants, particularly vitamin E, have failed to protect against atherosclerotic diseases. A striking exception is probucol, which retards atherosclerosis in carotid arteries and restenosis of coronary arteries after angioplasty. Because probucol has in vitro cellular-protective effects independent of inhibiting lipid oxidation, we investigated the mode of action of probucol in vivo. We used three models of vascular disease: apolipoprotein E-defi cient mice, a model of atherosclerosis; rabbit aortic balloon injury, a model of restenosis; and carotid injury in obese Zucker rats, a model of type 2 diabetes. Unexpectedly, we observed that the phenol moieties of probucol were insuffi cient, whereas its sulphur atoms were required for protection. Probucol and its sulphur-containing metabolite, but not a sulphur-free phenolic analogue, protected via cell-specifi c effects on inhibiting macrophage accumulation, stimulating reendothelialization, and inhibiting vascular smooth muscle cell proliferation. These processes were mediated via induction of heme oxygenase-1 (HO-1), an activity not shared by vitamin E. Our fi ndings identify HO-1 as the molecular target of probucol. They indicate 2-electron rather than radical (1-electron) oxidants as important contributors to atherogenesis, and point to novel lead compounds for therapeutic intervention against atherosclerotic diseases.
Redox Report, 2007
Accumulating evidence links hypertension and atherosclerotic vascular disease with the accumulation of oxidized, low-density lipoproteins and enhanced generation of reactive oxygen species (ROS) in the vessel wall. 1-3 ROS are generated as by-products of metabolism and rapidly react with cellular components, causing damage to membrane lipids, proteins and DNA. Endothelial cells generate superoxide anions (O 2 •-) and H 2 O 2 from xanthine oxidase, peroxidases, lipoxygenase, cyclooxygenase, nitric oxide synthase and NAD(P)H oxidases. 3 In atherosclerosis, accumulation of low-density lipoprotein (LDL), cholesterol and lipid deposits in the vessel wall lead to endothelial dysfunction, smooth muscle cell proliferation and fibrosis and lumen occlusion over decades. 2 Oxidation of arachidonic acid, a (ω-6) polyunsaturated fatty acid in LDL and cell membranes, can lead to the formation of cytotoxic aldehydes such as 4-hydroxy-2-nonenal (HNE), which further exacerbate atherogenesis through modification of ε-lysine residues in apolipoprotein B-100 of LDL leading to uptake by macrophages. Atherosclerotic lesions in humans and animal models contain high levels of HNE and amino acid adducts, making it a useful biomarker of lipid peroxidation and oxidative damage to proteins. 5,6 Moreover, recent evidence has shown that HNE can directly modulate intracellular signalling pathways, including mitogen-activated protein kinases (MAPK) and the transcription factors activator protein-1 (AP-1), nuclear factor-κB, (NF-κB) and NF-E2-related factor-2 (Nrf2). 7-9 In this context, HNE represents an important mediator of redox signalling in cells, either