Hydroxymethyl-Glutaryl Coenzyme A Reductase Inhibition Limits Cytomegalovirus Infection in Human Endothelial Cells

Potena, Luciano; Frascaroli, Giada; Grigioni, Francesco; Lazzarotto, Tiziana; Magnani, Gaia; Tomasi, Luciana; Coccolo, Fabio; Gabrielli, Liliana; Magelli, Carlo; Landini, Maria Paola; Branzi, Angelo

doi:10.1161/01.cir.0000109485.79183.81

Cited by 85 publications

(68 citation statements)

References 28 publications

(42 reference statements)

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“…Indeed, Coxsackie virus and human cytomegalovirus contain proteins that share amino acid sequences with human GAD65, which is strongly expressed in the pancreas 7,8 , and antigenic mimicry may explain the known association of human leukocyte antigen (HLA) haplotype and disease development 5 . However, several viruses suspected to be associated with diabetes do not contain any known cross-reactive e pitopes 5 , and approximately 50% of the European population is infected with human cytomegalovirus 9 without being diabetic, although human cytomegalovirus has a crossreactive epitope with the beta islet antigen GAD65 (ref. 5).…”

mentioning

confidence: 99%

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Lang

Recher

Junt

et al. 2005

Nat Med

346

258

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Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8 + T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-α production. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease.

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mentioning

confidence: 99%

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Lang

Recher

Junt

et al. 2005

Nat Med

346

258

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“…Interestingly, statins are known to exert anti-inflammatory effects independent of cholesterol-lowering properties. Moreover, they have been shown to inhibit CMV replication, viral antigen expression, and presentation, which may also influence the amount of antigen-dependent effector T cells (27).…”

Section: Discussionmentioning

confidence: 99%

Cytomegalovirus-Induced Effector T Cells Cause Endothelial Cell Damage

Berg¹,

Yong²,

Remmerswaal³

et al. 2012

Clin. Vaccine Immunol.

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ABSTRACTHuman cytomegalovirus (CMV) infection has been linked to inflammatory diseases that involve vascular endothelial cell damage, but definitive proof for a direct cytopathic effect of CMV in these diseases is lacking. CMV infection is associated with a strong increase in both CD4+and CD8+T cells with constitutive effector functions that can perpetuate systemic inflammation. We investigated whether CMV-induced immune responses could lead to endothelial damage in humans. We found that terminally differentiated effector CD4+and CD8+T cells, formed during primary CMV infection and maintained throughout latency, express high levels of CX3CR1 and CXCR3. The ligands of these receptors, fractalkine and IP-10, respectively, are expressed by activated endothelial cells. Peripheral blood mononuclear cells (PBMC) stimulated with CMV antigen produced soluble factors that stimulated endothelial cells to produce both chemokines. Finally, effector cells migrated in a fractalkine- and IP-10-dependent fashion to activated endothelial cells and induced apoptosis in endothelial cells that were stimulated by supernatant from CMV-activated PBMC. Our findings offer an explanation for the accumulation of highly differentiated T cells near to the endothelium in CMV-infected individuals that may result in endothelial damage.

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“…In an EC and a VSMC model of Chlamydia pneumoniae-induced inflammation, cerivastatin significantly attenuates the upregulation of inflammatory mediators, through suppression of NF-jB activation (30,52). Similarly, in HUVECs infected with cytomegalovirus, exposure to fluvastatin attenuates NF-jB activation, leading to reduced viral replication (89).…”

Section: Fig 7 Effects Of Statins On Nadph Oxidase In Ec Statins Smentioning

confidence: 99%

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

Margaritis

Channon

Antoniades

2014

Antioxidants & Redox Signaling

116

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Significance: Endothelial dysfunction and the imbalance between nitric oxide (NO) and reactive oxygen species production in the vascular endothelium are important early steps in atherogenesis, a major socioeconomic health problem. Statins have well-established roles in primary and secondary prevention of cardiovascular disease (CVD), due to both their lipid-lowering capacity and their pleiotropic properties. It is therefore important to understand the mechanisms by which statins can modify endothelial function and affect atherogenesis. Recent Advances: In the last decade, the concept of statin pleiotropy has been reinforced by a large number of cell culture, animal, and translational studies. Statins have been shown to suppress the activity of pro-oxidant enzymes (such as NADPH oxidase) and pro-inflammatory transcriptional pathways in the endothelium. At the same time, they enhance endothelial NO synthase expression and activity while they also improve its enzymatic coupling. This leads to increased NO bioavailability and improved endothelial function. Critical Issues: Despite significant recent advances, the exact mechanisms of statin pleitropy are still only partially understood. The vast majority of the published literature relies on animal studies, while the actual mechanistic studies in humans are limited. Future Directions: The success of statins as endothelium redox-modifying agents with a direct impact on clinical outcome highlights the importance of the endothelium as a therapeutic target in CVD. Better understanding of the mechanisms that underlie endothelial dysfunction could lead to the design of novel therapeutic strategies that target the vascular endothelium for the prevention and treatment of CVD. Antioxid. Redox Signal. 20, 1198Signal. 20, -1215

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Hydroxymethyl-Glutaryl Coenzyme A Reductase Inhibition Limits Cytomegalovirus Infection in Human Endothelial Cells

Cited by 85 publications

References 28 publications

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Toll-like receptor engagement converts T-cell autoreactivity into overt autoimmune disease

Cytomegalovirus-Induced Effector T Cells Cause Endothelial Cell Damage

Statins as Regulators of Redox State in the Vascular Endothelium: Beyond Lipid Lowering

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