Showing papers on "Heme oxygenase published in 2005"
TL;DR: Understanding of the cellular and molecular mechanisms that regulate the production and mediate the physiological actions of CO has greatly advanced and many diseases, including neurodegenerations, hypertension, heart failure, and inflammation, have been linked to the abnormality in CO metabolism and function.
Abstract: Over the last decade, studies have unraveled many aspects of endogenous production and physiological functions of carbon monoxide (CO). The majority of endogenous CO is produced in a reaction catalyzed by the enzyme heme oxygenase (HO). Inducible HO (HO-1) and constitutive HO (HO-2) are mostly recognized for their roles in the oxidation of heme and production of CO and biliverdin, whereas the biological function of the third HO isoform, HO-3, is still unclear. The tissue type-specific distribution of these HO isoforms is largely linked to the specific biological actions of CO on different systems. CO functions as a signaling molecule in the neuronal system, involving the regulation of neurotransmitters and neuropeptide release, learning and memory, and odor response adaptation and many other neuronal activities. The vasorelaxant property and cardiac protection effect of CO have been documented. A plethora of studies have also shown the importance of the roles of CO in the immune, respiratory, reproductive, gastrointestinal, kidney, and liver systems. Our understanding of the cellular and molecular mechanisms that regulate the production and mediate the physiological actions of CO has greatly advanced. Many diseases, including neurodegenerations, hypertension, heart failure, and inflammation, have been linked to the abnormality in CO metabolism and function. Enhancement of endogenous CO production and direct delivery of exogenous CO have found their applications in many health research fields and clinical settings. Future studies will further clarify the gasotransmitter role of CO, provide insight into the pathogenic mechanisms of many CO abnormality-related diseases, and pave the way for innovative preventive and therapeutic strategies based on the physiologic effects of CO.
855 citations
TL;DR: Free heme acts as a pro-inflammatory molecule and heme-induced inflammation is involved in the pathology of diverse conditions; such as renal failure, arteriosclerosis, and complications after artificial blood transfusion, peritoneal endometriosis, and heart transplant failure.
746 citations
TL;DR: This work shows that synthetic triterpenoid analogues of oleanolic acid are extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress.
Abstract: A series of synthetic triterpenoid (TP) analogues of oleanolic acid are powerful inhibitors of cellular inflammatory processes such as the induction by IFN-γ of inducible nitric oxide synthase (iNOS) and of cyclooxygenase 2 in mouse macrophages. Here, we show that these analogues are also extremely potent inducers of the phase 2 response [e.g., elevation of NAD(P)H-quinone oxidoreductase and heme oxygenase 1], which is a major protector of cells against oxidative and electrophile stress. Moreover, like previously identified phase 2 inducers, the TP analogues use the antioxidant response element–Nrf2–Keap1 signaling pathway. Thus, induction of the phase 2 response and suppression of the iNOS induction was abrogated in nrf2–/– and keap1–/– mouse embryonic fibroblasts. The high potency of TP analogues in inducing the phase 2 response and blocking inflammation depends on the presence of activated Michael reaction (enone) functions at critical positions in rings A and C. The most potent TP doubles NAD(P)H–quinone oxidoreductase in murine hepatoma cells at 0.28 nM and has an IC50 for suppression of iNOS induction in primary mouse macrophages of 0.0035 nM. The direct interaction of this TP with thiol groups of the Keap1 sensor for inducers is demonstrated spectroscopically. The antiinflammatory and phase 2 inducer potencies of 18 TP are closely linearly correlated (r2 = 0.91) over 6 orders of magnitude of concentration. Thus, in addition to blocking inflammation and promoting differentiation, these TP exhibit another very important protective property: the induction of the phase 2 response.
582 citations
TL;DR: It is suggested that resveratrol augments cellular antioxidant defense capacity through induction of HO-1 via Nrf2-ARE signaling, thereby protecting PC12 cells from oxidative stress.
405 citations
TL;DR: This demonstration is the first showing that a physiologically inducible vector expressing of HO-1 genes improves the survival of stem cells in myocardial ischemia.
386 citations
TL;DR: Results indicate that CO liberated by CORM‐2 andCORM‐3 significantly suppresses the inflammatory response elicited by LPS in cultured macrophages and suggest that CO carriers can be used as an effective strategy to modulate inflammation.
Abstract: The enzyme heme oxygenase-1 (HO-1) is a cytoprotective and anti-inflammatory protein that degrades heme to produce biliverdin/bilirubin, ferrous iron and carbon monoxide (CO). The anti-inflammatory properties of HO-1 are related to inhibition of adhesion molecule expression and reduction of oxidative stress, while exogenous CO gas treatment decreases the production of inflammatory mediators such as cytokines and nitric oxide (NO). CO-releasing molecules (CO-RMs) are a novel group of substances identified by our group that are capable of modulating physiological functions via the liberation of CO. We aimed in this study to examine the potential anti-inflammatory characteristics of CORM-2 and CORM-3 in an in vitro model of lipopolysaccharide (LPS)-stimulated murine macrophages. Stimulation of RAW264.7 macrophages with LPS resulted in increased expression of inducible NO synthase (iNOS) and production of nitrite. CORM-2 or CORM-3 (10-100 microM) reduced nitrite generation in a concentration-dependent manner but did not affect the protein levels of iNOS. CORM-3 also decreased nitrite levels when added 3 or 6 h after LPS exposure. CORM-2 or CORM-3 did not cause any evident cytotoxicity and produced an increase in HO-1 expression and heme oxygenase activity; this effect was completely prevented by the thiol donor N-acetylcysteine. CORM-3 also considerably reduced the levels of tumor necrosis factor-alpha, another mediator of the inflammatory response. The inhibitory effects of CORM-2 and CORM-3 were not observed when the inactive compounds, which do not release CO, were coincubated with LPS. These results indicate that CO liberated by CORM-2 and CORM-3 significantly suppresses the inflammatory response elicited by LPS in cultured macrophages and suggest that CO carriers can be used as an effective strategy to modulate inflammation.
371 citations
TL;DR: Large amounts of HO proteins from human and rat can now be prepared in truncated soluble form, and the crystal structures of some HO proteins have been determined, which have greatly facilitated the understanding of the mechanisms of individual steps of the HO reaction.
371 citations
TL;DR: It is suggested that pharmacological agents that regulate HO activity or HO-1 gene delivery itself may become powerful tools for preventing the onset or progression of certain cardiovascular pathologies.
367 citations
TL;DR: The capacity of HO-1 is identified, for the first time, to block maturation of DCs and to inhibit proinflammatory and allogeneic immune responses while preserving IL-10 production.
328 citations
TL;DR: These studies are the first to investigate the induction of the HO-1 and Nrf2/ARE pathways by CDDO and CDDO-Im, and the results suggest that further in vivo studies are needed to explore the chemopreventive and chemotherapeutic potential of the triterpenoids.
Abstract: The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and its derivative 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im) are multifunctional molecules with potent antiproliferative, differentiating, and anti-inflammatory activities. At nanomolar concentrations, these agents rapidly increase the expression of the cytoprotective heme oxygenase-1 (HO-1) enzyme in vitro and in vivo. Transfection studies using a series of reporter constructs show that activation of the human HO-1 promoter by the triterpenoids requires an antioxidant response element (ARE), a cyclic AMP response element, and an E Box sequence. Inactivation of one of these response elements alone partially reduces HO-1 induction, but mutations in all three sequences entirely eliminate promoter activity in response to the triterpenoids. Treatment with CDDO-Im also elevates protein levels of Nrf2, a transcription factor previously shown to bind ARE sequences, and increases expression of a number of antioxidant and detoxification genes regulated by Nrf2. The triterpenoids also reduce the formation of reactive oxygen species in cells challenged with tert-butyl hydroperoxide, but this cytoprotective activity is absent in Nrf2 deficient cells. These studies are the first to investigate the induction of the HO-1 and Nrf2/ARE pathways by CDDO and CDDO-Im, and our results suggest that further in vivo studies are needed to explore the chemopreventive and chemotherapeutic potential of the triterpenoids.
297 citations
TL;DR: Observations in experimental diabetes suggest that the vascular cytoprotective mechanism of HO-1 against oxidative stress requires an increase in EC-SOD and catalase.
Abstract: Increased heme oxygenase (HO)-1 activity attenuates endothelial cell apoptosis and decreases superoxide anion (O2-) formation in experimental diabetes by unknown mechanisms. We examined the effect of HO-1 protein and HO activity on extracellular SOD (EC-SOD), catalase, O2-, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) levels and vascular responses to ACh in control and diabetic rats. Vascular EC-SOD and plasma catalase activities were significantly reduced in diabetic compared with nondiabetic rats (P < 0.05). Upregulation of HO-1 expression by intermittent administration of cobalt protoporphyrin, an inducer of HO-1 protein and activity, resulted in a robust increase in EC-SOD but no significant change in Cu-Zn-SOD. Administration of tin mesoporphyrin, an inhibitor of HO-1 activity, decreased EC-SOD protein. Increased HO-1 activity in diabetic rats was associated with a decrease in iNOS but increases in eNOS and plasma catalase activity. On the other hand, aortic ring segments from diabetic rats exhibited a significant reduction in vascular relaxation to ACh, which was reversed with cobalt protoporphyrin treatment. These data demonstrate that an increase in HO-1 protein and activity, i.e., CO and bilirubin production, in diabetic rats brings about a robust increase in EC-SOD, catalase, and eNOS with a concomitant increase in endothelial relaxation and a decrease in O2-. These observations in experimental diabetes suggest that the vascular cytoprotective mechanism of HO-1 against oxidative stress requires an increase in EC-SOD and catalase.
TL;DR: Results suggest quercetin should provide therapeutic benefits for suppression of inflammatory-related neuronal injury in neurodegenerative diseases.
TL;DR: Findings indicate that bilirubin can act as an effective agent to reduce mortality and counteract hypotension elicited by endotoxin through mechanisms involving a decreased NOS2 induction secondary to inhibition of NAD(P)H oxidase.
Abstract: SPECIFIC AIMSThis study is devoted to the investigation of a potential protective role for bilirubin, one of the products of heme degradation by the enzyme heme oxygenase, in endotoxic shock. The r...
TL;DR: The study shows that the addition of byproducts of heme degradation with different mechanisms of action provides enhanced protection against transplant‐associated cold I/R injury of heart and kidney grafts.
01 May 2005
TL;DR: The activation of toll-like receptors (TLR) on Kupffer cells may provide the triggering signal for pro-inflammatory responses in the I/R injury sequence, and dissecting TLR downstream signaling pathways plays a fundamental role in exploring novel therapeutic strategies based on the concept that hepatic I-R injury represents a case for host "innate" immunity.
Abstract: Ischemia/reperfusion (I/R) injury is a multifactorial process detrimental to liver graft function. An understanding of the mechanisms involved in I/R injury is essential for the design of therapeutic strategies to improve the outcome of liver transplantation. The generation of reactive oxygen species subsequent to reoxygenation inflicts tissue damage and initiates a cellular cascade leading to inflammation, cell death, and ultimate organ failure. The accruing evidence suggests that Kupffer cells and T cells mediate the activation of neutrophil inflammatory responses. Activated neutrophils infiltrate the injured liver in parallel with increased expression of adhesion molecules on endothelial cells. The heme oxygenase (HO) system is among the most critical of the cytoprotective mechanisms activated during the cellular stress, exerting anti-oxidant and anti-inflammatory functions, modulating the cell cycle, and maintaining the microcirculation. The activation of toll-like receptors (TLR) on Kupffer cells may provide the triggering signal for pro-inflammatory responses in the I/R injury sequence. Indeed, dissecting TLR downstream signaling pathways plays a fundamental role in exploring novel therapeutic strategies based on the concept that hepatic I/R injury represents a case for host "innate" immunity.
TL;DR: Hme oxygenase-1 protein expression can occur in the lung in response to oxidative stress associated with infection, altered oxygen tension, and inflammatory diseases, and HO-1 remains widely regarded as a protective mechanism against oxidative tissue injury.
Abstract: Reactive oxygen species (ROS) may contribute to tissue damage in many pathophysiological conditions and participate in physiological signaling processes. The mechanisms by which cells sense prooxidant states, and activate signaling pathways leading to adaptive responses, remain incompletely understood. Bacteria contain several transcriptional regulators (e.g., OxyR) and a low-molecular-weight heat shock protein (HSP33), whose activity increases upon oxidation of critical sulfhydryl residues. These proteins participate in cellular adaptation to oxidative stress. In higher organisms, heme oxygenase-1 (HO-1) has been widely studied as a model for redox-regulated gene expression. Expression of HO-1 responds to chemical and physical agents that directly or indirectly generate ROS. Depletion of cellular reduced glutathione may act as a signal for HO-1 transcriptional activation. Furthermore, antioxidants and metal-chelating compounds can modulate HO-1 expression. Several signaling molecules (e.g., mitogen-activ...
TL;DR: Induction of HO-1 protein may participate in the protective mechanism of QE on oxidative stress (H(2)O(2))-induced apoptosis, and reduction of intracellular ROS production and mitochondria dysfunction with blocking apoptotic events were involved.
TL;DR: It is demonstrated that CO administration is effective as a therapeutic modality in mice with established chronic colitis and a specific signaling pathway, not previously identified, is delineated that involves an obligatory role for HO-1 induction in the protection afforded by CO.
Abstract: Heme oxygenase (HO)-1 and its metabolic product carbon monoxide (CO) play regulatory roles in acute inflammatory states. In this study, we demonstrate that CO administration is effective as a therapeutic modality in mice with established chronic colitis. CO administration ameliorates chronic intestinal inflammation in a T helper (Th)1-mediated model of murine colitis, interleukin (IL)-10-deficient (IL-10(-/-)) mice. In Th1-mediated inflammation, CO abrogates the synergistic effect of interferon (IFN)-gamma on lipopolysaccharide-induced IL-12 p40 in murine macrophages and alters IFN-gamma signaling by inhibiting a member of the IFN regulatory factor (IRF) family of transcription factors, IRF-8. A specific signaling pathway, not previously identified, is delineated that involves an obligatory role for HO-1 induction in the protection afforded by CO. Moreover, CO antagonizes the inhibitory effect of IFN-gamma on HO-1 expression in macrophages. In macrophages and in Th1-mediated colitis, pharmacologic induction of HO-1 recapitulates the immunosuppressive effects of CO. In conclusion, this study begins to elucidate potential etiologic and therapeutic implications of CO and the HO-1 pathway in chronic inflammatory bowel diseases.
TL;DR: The history of heme oxygenase research, the role of this enzyme in the lung, and related new developments to look forward to in the fields of pulmonary and critical care medicine are introduced.
Abstract: As aspects of basic science come to play an increasingly prominent role in clinical medicine, heme oxygenase-1 is one of several molecules emerging as a central player in diseases of the lung and intensive care unit. Although the apparent raison d'etre of this enzyme is to dispose of heme, its activity results in cytoprotection against oxidative injury and cellular stresses. As the lung interfaces directly with an oxidizing environment, it is expected that heme oxygenase-1 would be involved in many aspects of lung health and disease. The protective effects of heme oxygenase-1 and products of its enzymatic activity, including carbon monoxide, biliverdin and bilirubin, and ferritin, have opened the door to potential therapeutic and disease-monitoring possibilities that one day may be applicable to pulmonary medicine. This article introduces readers to the history of heme oxygenase research, the role of this enzyme in the lung, and related new developments to look forward to in the fields of pulmonary and critical care medicine.
TL;DR: The data show that HIF-1 activation induces substantial HO-1 expression that is associated with attenuated proinflammatory chemokine production by microvascular endothelium in vitro and in vivo.
Abstract: The CXC chemokine IL-8, which promotes adhesion, activation, and transmigration of polymorphonuclear neutrophils (PMN), has been associated with production of tissue injury in reperfused myocardium...
TL;DR: The relationship of HO and cardiovascular disease, especially atherosclerosis, gene-targeting approaches in animal models, and the potential for and concern about HO-1 as a novel therapeutic target for cardiovascular diseases are highlighted.
Abstract: 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 properties, and to generate carbon monoxide, which has antiproliferative and antiinflammatory as well as vasodilatory properties. Herein, I highlight the relationship of HO and cardiovascular disease, especially atherosclerosis, gene-targeting approaches in animal models, and the potential for and concern about HO-1 as a novel therapeutic target for cardiovascular diseases.
TL;DR: The results demonstrated that pretreatment with resveratrol markedly reduced infarct size 24 h after myocardial infarction (MI) and increased capillary density in the peri-infarct myocardium along with better left ventricular function 4 days after MI compared with vehicle-treated control.
TL;DR: The scope of this review is limited to focus on molecular mechanisms underlyingHO-1 expression and the significance of targeted induction of HO-1 as a strategy to achieve chemoprevention and chemoprotection.
Abstract: Heme oxygenase (HO)-1, involved in the heme degradation process, is an important antioxidant enzyme. The induction of HO-1 gene expression, in response to diverse oxidative stimuli, represents a critical event in adaptive cellular response. Experimental models of various diseases, including acute inflammation, atherosclerosis, degenerative diseases, and carcinogenesis, have demonstrated that the induction of HO-1 can prevent or mitigate the symptoms associated with these ailments. Recent progress in our understanding of cellular signaling networks as critical modulators of gene transcription sheds light on the molecular basis of HO-1 gene expression. A panel of redox-sensitive transcription factors such as activator protein-1, nuclear factor- κB, and nuclear factor E2-related factor-2, and some of the upstream kinases have been identified as regulators of HO-1 gene induction. The scope of this review is limited to focus on molecular mechanisms underlying HO-1 expression and the significance of targeted in...
TL;DR: A number of heritable polymorphisms of pro-oxidant enzymes have been identified and found to modulate ROS production and, thereby, the risk of atherothrombotic cardiovascular disease in individuals with these genetic polymorphisms.
Abstract: In the vasculature, reactive oxygen species (ROS) generated by both mitochondrial respiration and enzymatic sources serve as integral components of cellular signaling and homeostatic mechanisms. Because ROS are highly reactive biomolecules, the cellular redox milieu is carefully maintained by small-molecule antioxidants and antioxidant enzymes to prevent the deleterious consequences of ROS excess. When this redox balance is perturbed, because of either increased ROS production or decreased antioxidant capacity, oxidant stress is increased in the vessel wall and, if not offset, vascular dysfunction ensues. A number of heritable polymorphisms of pro-oxidant enzymes, including 5-lipoxygenase, cyclooxygenase-2, nitric oxide synthase-3, and NAD(P)H oxidase, have been identified and found to modulate ROS production and, thereby, the risk of atherothrombotic cardiovascular disease in individuals with these genetic polymorphisms. Similarly, heritable deficiency of the antioxidant enzymes catalase, glutathione peroxidases, glutathione-S-transferases, heme oxygenase, and glucose-6-phosphate dehydrogenase favors ROS accumulation, and has been associated with an increased risk of vascular disease. Individually, each of these polymorphisms imposes a state of uncompensated oxidant stress on the vasculature and collectively comprise the oxidative enzymopathies.
TL;DR: Results indicate that LPS-induced HO-1 expression in human monocytic cells requires Nrf2 and PKC.
Abstract: Monocytes play a key role in mobilization of the immune response during sepsis. In response to LPS, monocytes produce both proinflammatory mediators and regulatory proteins that counteract the inflammation and oxidative stress. In murine macrophages, LPS stimulates expression of heme oxygenase 1 (HO-1), a cytoprotective enzyme that catalyzes the degradation of heme. The HO-1 5′-untranslated region, similarly to other cytoprotective genes, contains antioxidant-response elements (AREs) that can bind the transcription factor NF-E2-related factor 2 (Nrf2). At present, the role of Nrf2 in LPS-induced HO-1 expression in monocytic cells has not been investigated. In this study, LPS induced HO-1 mRNA and protein expression in human monocytes and THP-1 cells. Nrf2 translocated from the cytosol to the nucleus in response to LPS and bound to the ARE site in the human HO-1 promoter. In addition, a dominant negative Nrf2 mutant inhibited LPS-induced HO-1 mRNA expression but not TNF-α mRNA expression in THP-1 cells. Ro-31-8220, a pan-protein kinase C (PKC) inhibitor, and Go6976, a classical PKC inhibitor, blunted LPS-induced HO-1 mRNA expression in monocytes and THP-1 cells. Both PKC inhibitors also blocked LPS-induced Nrf2 binding to the ARE. These results indicate that LPS-induced HO-1 expression in human monocytic cells requires Nrf2 and PKC.
TL;DR: An increase in circulating endothelial cell sloughing, superoxide anion, and vasoconstriction in diabetic rats can be prevented by administration of D-4F, which is associated with an increase in 2 antioxidant proteins, HO-1 and EC-SOD.
Abstract: Background— Apolipoprotein A1 mimetic peptide, synthesized from D-amino acid (D-4F), enhances the ability of HDL to protect LDL against oxidation in atherosclerotic animals. Methods and Results— We investigated the mechanisms by which D-4F provides antioxidant effects in a diabetic model. Sprague-Dawley rats developed diabetes with administration of streptozotocin (STZ). We examined the effects of daily D-4F (100 μg/100 g of body weight, intraperitoneal injection) on superoxide (O2−), extracellular superoxide dismutase (EC-SOD), vascular heme oxygenase (HO-1 and HO-2) levels, and circulating endothelial cells in diabetic rats. In response to D-4F, both the quantity and activity of HO-1 were increased. O2− levels were elevated in diabetic rats (74.8±8×103 cpm/10 mg protein) compared with controls (38.1±8×103 cpm/10 mg protein; P<0.01). D-4F decreased O2− levels to 13.23±1×103 (P<0.05 compared with untreated diabetics). The average number of circulating endothelial cells was higher in diabetics (50±6 cells/...
TL;DR: In conclusion, this study highlights the importance of cross talk between HO‐1 and TLR system in the mechanism of hepatic IRI, which represents a case for innate immunity in which HO‐ 1 modulates proinflammatory responses that are triggered via TLR4 signaling, a putativeHO‐1 repressor.
TL;DR: It is suggested that resveratrol-mediated HO-1 expression occurs, at least in part, through the NF-kappaB pathway, which might contribute to resver atrol's vascular-protective effect at physiological concentrations after moderate red wine consumption.
TL;DR: It is hypothesized that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age‐related diseases.
Abstract: Efficient functioning of maintenance and repair processes seem to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, under control of several genes termed vitagenes. These include members of the heat shock protein system, and there is now evidence that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human conditions, including inflammation, neurodegenerative disorders, and aging. Among the various heat shock proteins, heme oxygenase-1 has received considerable attention; it has been recently demonstrated that heme oxygenase-1 induction, by generating the vasoactive molecule carbon monoxide and the potent antioxidant bilirubin, could represent a protective system potentially active against brain oxidative injury. Acetyl-L-carnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, we report here that treatment of astrocytes with acetyl-L-carnitine induces heme oxygenase-1 in a dose- and time-dependent manner and that this effect was associated with up-regulation of heat shock protein 60 as well as high expression of the redox-sensitive transcription factor Nrf2 in the nuclear fraction of treated cells. In addition, we show that addition of acetyl-L-carnitine to astrocytes, prior to proinflammatory lipopolysaccharide- and interferon-γ-induced nitrosative stress, prevents changes in mitochondrial respiratory chain complex activity, protein nitrosation and antioxidant status induced by inflammatory cytokine insult. Given the broad cytoprotective properties of the heat shock response, molecules inducing this defense mechanism appear to be possible candidates for novel cytoprotective strategies. Particularly, manipulation of endogenous cellular defense mechanisms via acetyl-L-carnitine may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration. We hypothesize that maintenance or recovery of the activity of vitagenes may delay the aging process and decrease the risk of age-related diseases. © 2005 Wiley-Liss, Inc.
TL;DR: Oxidized phospholipids contribute to vascular inflammation in murine arteries in vivo, initiating atherogenic chemokine expression that leads to monocyte adhesion; therefore, they can be regarded as triggers of the inflammatory process in atherosclerosis.
Abstract: Objective—Lipoprotein-derived phospholipid oxidation products have been implicated as candidate triggers of the inflammatory process in atherosclerosis. However, in vivo evidence regarding the impact of oxidized phospholipids on the artery wall thus far has been elusive. Therefore, the aim of this study was to investigate if structurally defined oxidized phospholipids induce expression of atherogenic chemokines and monocyte adhesion in intact murine arteries. Methods and Results—To model the accumulation of oxidized phospholipids in the arterial wall, oxidized 1-palmitoyl2-arachidonoyl-sn-3-glycero-phosphorylcholine (OxPAPC) was topically applied to carotid arteries in mice using pluronic gel. Using quantitative reverse-transcriptase polymerase chain reaction (PCR) and immunohistochemistry, we show that OxPAPC induced a set of atherosclerosis-related genes, including monocyte chemotactic protein 1 (MCP-1) and keratinocyte-derived chemokine (KC), tissue factor (TF), interleukin 6 (IL-6), heme oxygenase 1 (HO-1), and early growth response 1 (EGR-1). OxPAPC-regulated chemokines were also expressed in atherosclerotic lesions of apolipoprotein E-deficient (ApoE / ) mice. In isolated perfused carotid arteries, OxPAPC triggered rolling and firm adhesion of monocytes in a P-selectin and KC-dependent manner. Conclusion—Oxidized phospholipids contribute to vascular inflammation in murine arteries in vivo, initiating atherogenic chemokine expression that leads to monocyte adhesion; therefore, they can be regarded as triggers of the inflammatory process in atherosclerosis. (Arterioscler Thromb Vasc Biol. 2005;25:633-638.)