Heme Induces Heme Oxygenase 1 via Nrf2

Boyle, Joseph J.; Johns, Michael; Lo, Jonathan; Chiodini, Alessandra; Ambrose, Nicola; Evans, Paul C.; Mason, Justin C.; Haskard, Dorian O.

doi:10.1161/atvbaha.111.225813

Cited by 109 publications

(40 citation statements)

References 35 publications

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“…The remaining 39% of aortic CD11b + F4/80 + cells were classified as CD11b + F4/80 + CD86 + M1 MΦs and 22% expressed the M2 marker CD206 (Kadl et al, 2010). The proposed phenotype of Mox MΦs closely resembles the phenotype of the recently proposed hemorrhage-associated MΦs (Mha; Boyle et al, 2009; Boyle et al, 2011). Human monocyte-derived MΦs that are treated in vitro with hapto-hemoglobin complexes or oxidized red blood cells were found to upregulate CD163, HO-1, and IL-10 in an Nrf2-dependent manner (Boyle et al, 2009).…”

Section: Mox/mha Subset Of Macrophagessupporting

confidence: 77%

Phenotypic and Functional Heterogeneity of Macrophages and Dendritic Cell Subsets in the Healthy and Atherosclerosis-Prone Aorta

Butcher¹,

Galkina²

2012

Front. Physio.

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Atherosclerosis continues to be the leading cause of cardiovascular disease. Development of atherosclerosis depends on chronic inflammation in the aorta and multiple immune cells are involved in this process. Importantly, resident macrophages and dendritic cells (DCs) are present within the healthy aorta, but the functions of these cells remain poorly characterized. Local inflammation within the aortic wall promotes the recruitment of monocytes and DC precursors to the aorta and micro-environmental factors direct the differentiation of these emigrated cells into multiple subsets of macrophages and DCs. Recent data suggest that several populations of macrophages and DCs can co-exist within the aorta. Although the functions of M1, M2, Mox, and M4 macrophages are well characterized in vitro, there is a limited set of data on the role of these populations in atherogenesis in vivo. Recent studies on the origin and the potential role of aortic DCs provide novel insights into the biology of aortic DC subsets and prospective mechanisms of the immune response in atherosclerosis. This review integrates the results of experiments analyzing heterogeneity of DCs and macrophage subsets in healthy and diseased vessels and briefly discusses the known and potential functions of these cells in atherogenesis.

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Section: Mox/mha Subset Of Macrophagessupporting

confidence: 77%

Phenotypic and Functional Heterogeneity of Macrophages and Dendritic Cell Subsets in the Healthy and Atherosclerosis-Prone Aorta

Butcher¹,

Galkina²

2012

Front. Physio.

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“…Macrophages associated with hemorrhage areas were characterized as CD163 high and HLA-DRlow (Boyle et al, 2011b). Moreover, as a consequence of enhanced Hb clearance, HA-mac macrophages have increased HO-1 and FPN expression, leading to facilitated heme catabolism and reduced intracellular free iron.…”

Section: Effect Of Iron On Main Players In Atherogenesismentioning

confidence: 99%

“…HA-mac macrophages are distinct from the macrophages found in the lipid core and seem to play an atheroprotective role. In vitro stimulation of monocytes with Hb-Hp complexes showed a differentiation toward an HA-mac phenotype, suggesting that Hb released upon hemorrhage might model monocytes recruited to the lesion toward a specific HA-mac subtype (Boyle et al, 2011b). After treatment of human blood monocytes with heme HO-1and CD163 are upregulated, a process depending onNrf2 and the activating transcription factor 1 (Boyle et al, 2011a).…”

Section: Effect Of Iron On Main Players In Atherogenesismentioning

confidence: 99%

Atherogenesis and iron: from epidemiology to cellular level

et al. 2014

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Iron accumulates in human atherosclerotic lesions but whether it is a cause or simply a downstream consequence of the atheroma formation has been an open question for decades. According to the so called “iron hypothesis,” iron is believed to be detrimental for the cardiovascular system, thus promoting atherosclerosis development and progression. Iron, in its catalytically active form, can participate in the generation of reactive oxygen species and induce lipid-peroxidation, triggering endothelial activation, smooth muscle cell proliferation and macrophage activation; all of these processes are considered to be proatherogenic. On the other hand, the observation that hemochromatotic patients, affected by life-long iron overload, do not show any increased incidence of atherosclerosis is perceived as the most convincing evidence against the “iron hypothesis.” Epidemiological studies and data from animal models provided conflicting evidences about the role of iron in atherogenesis. Therefore, more careful studies are needed in which issues like the source and the compartmentalization of iron will be addressed. This review article summarizes what we have learnt about iron and atherosclerosis from epidemiological studies, animal models and cellular systems and highlights the rather contributory than innocent role of iron in atherogenesis.

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“…Boyle et al (2009, 2011) were the first to explore the effects of intraplaque hemorrhage on macrophage phenotype. Advanced atherosclerotic plaques were examined for immunostaining for CD163 and HLA-DR, a sign of macrophage activation.…”

Section: Intraplaque Hemorrhage and Macrophage Polarizationmentioning

confidence: 99%

The role of iron metabolism as a mediator of macrophage inflammation and lipid handling in atherosclerosis

Habib

Finn

2014

Front. Pharmacol.

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Iron is an essential mineral needed for normal physiologic processes. While its function in oxygen transport and other important physiologic processes is well known, less is understood about its role in inflammatory diseases such as atherosclerosis. Existing paradigms suggest iron as a driver of atherosclerosis through its actions as a pro-oxidant capable of causing lipid oxidation and tissue damage. Recently we and others have identified hemoglobin (Hb) derived iron as an important factor in determining macrophage differentiation and function in areas of intraplaque hemorrhage within human atherosclerosis. Hb associated macrophages, M(Hb), are distinct from traditional macrophage foam cells because they do not contain large amounts of lipid or inflammatory cytokines, are characterized by high levels of expression of mannose receptor (CD206) and CD163 in addition to producing anti-inflammatory cytokines such as IL-10. Despite the well-known role of iron as an catalyst capable of producing lipid peroxidation through generation of reactive oxygen species (ROS) such as hydroxyl radical, we and others have shown that macrophages in areas of intraplaque hemorrhage demonstrate reduced intracellular iron and ROS which triggers production of anti-inflammatory cytokines as well as genes involved in cholesterol eﬄux. These data suggest that manipulation of macrophage iron itself may be a promising pharmacologic target for atherosclerosis prevention through its effects on macrophage inflammation and lipid metabolism. In this review we will summarize the current understanding of iron as it relates to plaque inflammation and discuss how further exploration of this subject may lead to new therapies for atherosclerosis.

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Heme Induces Heme Oxygenase 1 via Nrf2

Cited by 109 publications

References 35 publications

Phenotypic and Functional Heterogeneity of Macrophages and Dendritic Cell Subsets in the Healthy and Atherosclerosis-Prone Aorta

Phenotypic and Functional Heterogeneity of Macrophages and Dendritic Cell Subsets in the Healthy and Atherosclerosis-Prone Aorta

Atherogenesis and iron: from epidemiology to cellular level

The role of iron metabolism as a mediator of macrophage inflammation and lipid handling in atherosclerosis

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