Vasculitis, Atherosclerosis, and Altered HDL Composition in Heme-Oxygenase-1-Knockout Mice

Ishikawa, Kazunobu; Navab, Mohamad; Lusis, Aldons J.

doi:10.1155/2012/948203

Cited by 25 publications

(19 citation statements)

References 33 publications

(38 reference statements)

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“…41 HO-1 À / À mice generally have reduced body weight and are prone to develop vasculitis, atherosclerosis, anemia, and hepatic and renal iron accumulation, leading to tissue damage and chronic inflammation, along with organ injury/failure. 39,[42][43][44] HO-1 À / À mice typically die within the first 6 months. 44 Therefore, we decided to use HO-1 flox/flox mice that lack leukocytic HO-1 in this study to ensure that our results were not influenced by genetically caused illnesses.…”

Section: Discussionmentioning

confidence: 99%

Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation

et al. 2016

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Heme oxygenase-1 (HO-1) has been shown to display anti-inflammatory properties in models of acute pulmonary inflammation. For the first time, we investigated the role of leukocytic HO-1 using a model of HO-1(flox/flox) mice lacking leukocytic HO-1 that were subjected to lipopolysaccharide (LPS)-induced acute pulmonary inflammation. Immunohistology and flow cytometry demonstrated that activation of HO-1 using hemin decreased migration of polymorphonuclear leukocytes (PMNs) to the lung interstitium and bronchoalveolar lavage (BAL) in the wild-type and, surprisingly, also in HO-1(flox/flox) mice, emphasizing the anti-inflammatory potential of nonmyeloid HO-1. Nevertheless, hemin reduced the CXCL1, CXCL2/3, tumor necrosis factor-α (TNFα), and interleukin 6 (IL6) levels in both animal strains. Microvascular permeability was attenuated by hemin in wild-type and HO-1(flox/flox) mice, indicating a crucial role of non-myeloid HO-1 in endothelial integrity. The determination of the activity of HO-1 in mouse lungs revealed no compensatory increase in the HO-1(flox/flox) mice. Topical administration of hemin via inhalation reduced the dose required to attenuate PMN migration and microvascular permeability by a factor of 40, emphasizing its clinical potential. In addition, HO-1 stimulation was protective against pulmonary inflammation when initiated after the inflammatory stimulus. In conclusion, nonmyeloid HO-1 is crucial for the anti-inflammatory effect of this enzyme on PMN migration to different compartments of the lung and on microvascular permeability.

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Section: Discussionmentioning

confidence: 99%

Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation

et al. 2016

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“…Using systemic manipulation of either HO-1 expression or activity, some studies suggested that HO-1 plays a vital role in atherosclerosis initiation and development. HO-1-null mice show a noteworthy increase in plasma lipid hydroperoxides [ 44 ]. Similarly, rabbits treated with SnPP, an HO-1 inhibitor, exhibit a significant lipid deposits in abdominal aortic plaques [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Clopidogrel Protects Endothelium by Hindering TNFα-Induced VCAM-1 Expression through CaMKKβ/AMPK/Nrf2 Pathway

Yang

Zhao

Tian

2016

Journal of Diabetes Research

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Clopidogrel (INN), an oral antiplatelet drug, has been revealed to have a number of biological properties, for instance, anti-inflammation and antioxidation. Oxidative stress plays an imperative role in inflammation, diabetes mellitus, atherosclerosis, and cancer. In the present study, human aortic endothelial cells (HAECs) were employed to explore the anti-inflammatory activity of INN. INN reduced TNFα-induced reactive oxygen species (ROS) generation and time-dependently prompted the expression and activity of heme oxygenase 1 (HO-1). Cellular glutathione (GSH) levels were augmented by INN. shHO-1 blocked the INN suppression of TNFα-induced HL-60 cell adhesion. The CaMKKβ/AMPK pathway and Nrf2 transcriptional factor were implicated in the induction of HO-1 by INN. Additionally, TNFα dramatically augmented VCAM-1 expression at protein and mRNA levels. INN treatment strikingly repressed TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Compound C, an AMPK inhibitor, and shNrf2 abolished TNFα-induced expression of VCAM-1 and HL-60 cell adhesion. Our data suggest that INN diminishes TNFα-stimulated VCAM-1 expression at least in part via HO-1 induction, which is CaMKKβ/AMPK pathway-dependent.

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“…The anti-atherogenic role of HO-1 has been reported in various studies. Pharmacological inhibition or knockdown of HO-1 show significant increases in lesion formation and further accelerates atherosclerosis in ApoE null mice [ 51 ], Watanabe heritable hyperlipidemic rabbits (WHHL) [ 52 ] and aortitis in chow-fed old C57BL/6 mice [ 53 ]. Apart from that, it has been demonstrated that upregulation of HO-1 genes expression by intraventricular administration of AdProT in mice has the capability to attenuate the development of atherosclerosis by reducing macrophages infiltration [ 54 ].…”

Section: Nrf2 and Macrophage Foam Cells Formationmentioning

confidence: 99%

Oxidative Stress in Cardiovascular Diseases: Involvement of Nrf2 Antioxidant Redox Signaling in Macrophage Foam Cells Formation

Ooi

Goh

Yap

2017

IJMS

104

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Oxidative stress is an important risk factor contributing to the pathogenesis of cardiovascular diseases. Oxidative stress that results from excessive reactive oxygen species (ROS) production accounts for impaired endothelial function, a process which promotes atherosclerotic lesion or fatty streaks formation (foam cells). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor involved in cellular redox homeostasis. Upon exposure to oxidative stress, Nrf2 is dissociated from its inhibitor Keap-1 and translocated into the nucleus, where it results in the transcriptional activation of cell defense genes. Nrf2 has been demonstrated to be involved in the protection against foam cells formation by regulating the expression of antioxidant proteins (HO-1, Prxs, and GPx1), ATP-binding cassette (ABC) efflux transporters (ABCA1 and ABCG1) and scavenger receptors (scavenger receptor class B (CD36), scavenger receptor class A (SR-A) and lectin-type oxidized LDL receptor (LOX-1)). However, Nrf2 has also been reported to exhibit pro-atherogenic effects. A better understanding on the mechanism of Nrf2 in oxidative stress-induced cardiac injury, as well as the regulation of cholesterol uptake and efflux, are required before it can serve as a novel therapeutic target for cardiovascular diseases prevention and treatment.

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Vasculitis, Atherosclerosis, and Altered HDL Composition in Heme-Oxygenase-1-Knockout Mice

Cited by 25 publications

References 33 publications

Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation

Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation

Clopidogrel Protects Endothelium by Hindering TNFα-Induced VCAM-1 Expression through CaMKKβ/AMPK/Nrf2 Pathway

Oxidative Stress in Cardiovascular Diseases: Involvement of Nrf2 Antioxidant Redox Signaling in Macrophage Foam Cells Formation

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