Herpesvirus Infection Accelerates Atherosclerosis in the Apolipoprotein E–Deficient Mouse

Alber, Dagmar; Powell, Kenneth L.; Vallance, Patrick; Goodwin, David A.; Grahame-Clarke, Cairistine

doi:10.1161/01.cir.102.7.779

Cited by 96 publications

(74 citation statements)

References 39 publications

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“…Inflammation, stress and infection are all known to be proatherogenic in apoE Ϫ/Ϫ mice (43)(44)(45)(46)(47)(48). In studying the possible specific actions of human CRP, it is therefore essential to be aware of, and if necessary exclude, intercurrent inflammatory pathology, such as the effects of occasional fighting (which is Cohort A 8 5 (4-7) n ϭ 4 NA 9 (5-12) n ϭ 8 11.1 (3.0-17.7) n ϭ 8 9 (5-12) n ϭ 21 NA 9 (5-12) n ϭ 11 10.9 (2.0-22.8) n ϭ 11 12 6 (3-10) n ϭ 7 NA 6 (1-8) n ϭ 18 7.8 (1.1-13.7) n ϭ 18 6 (3-11) n ϭ 17 NA 6 (4-11) n ϭ 17 17.1 (3.8-36.1) n ϭ 17, P Ͻ 0.005 16 6 (2-11) n ϭ 7 NA 6 (3-12) n ϭ 20 6.2 (1.2-14.2) n ϭ 20 6.5 (3-11) n ϭ 18 NA 6 (4-11) n ϭ 13 24.0 (9.8-31.2) n ϭ 13, P Ͻ 0.0001 20 6 (1-7) n ϭ 5 NA 4 (1-11) n ϭ 17 9.1 (1.3-12.6) n ϭ 17 5 (3-12) n ϭ 27 NA 4.5 (1-12) n ϭ 28 20.9 (1.8-41.1) n ϭ 28, P Ͻ 0.0001 Cohort B 12 NA ND 17.5 (2.9-21.9) n ϭ 5 ND 22.0 (11.2-32.6) n ϭ 5,…”

Section: Discussionmentioning

confidence: 99%

Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice

Hirschfield

Gallimore

Kahan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

178

123

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The association between circulating concentrations of C-reactive protein (CRP) and future atherothrombotic events has provoked speculation about a possible pathogenetic role of CRP. However, we show here that transgenic expression of human CRP had no effect on development, progression, or severity of spontaneous atherosclerosis, or on morbidity or mortality, in male apolipoprotein E (apoE)-deficient C57BL͞6 mice up to 56 weeks, despite deposition of human CRP and mouse complement component 3 in the plaques. Although female apoE knockouts develop atherosclerosis more rapidly than males, the human CRP transgene is under sex hormone control and is expressed at human levels only in males. We therefore studied only male mice. The concentration of mouse serum amyloid P component, an extremely sensitive systemic marker of inflammation, remained normal throughout except for transient spikes in response to fighting in a few animals, indicating that atherogenesis in this model is not associated with an acute-phase response. However, among human CRP transgenic mice, the circulating CRP concentration was higher in apoE knockouts than in wild-type controls. The higher CRP values were associated with substantially lower estradiol concentrations in the apoE-deficient animals. Human CRP transgene expression is thus up-regulated in apoE-deficient mice, apparently reflecting altered estrogen levels, despite the absence of other systemic signs of inflammation. Extrapolation to human pathology from this xenogeneic combination of human CRP with apoE deficiency-mediated mouse atherosclerosis must be guarded. Nevertheless, the present results do not suggest that human CRP is either proatherogenic or atheroprotective in vivo.atherosclerosis ͉ inflammation ͉ transgenic

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Section: Discussionmentioning

confidence: 99%

Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice

Hirschfield

Gallimore

Kahan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

178

123

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“…However, one study demonstrated that herpes infection accelerates atherosclerosis in apolipoprotein E-deficient mice, through an impairment of the eNOS pathway (72). We have recently demonstrated severe impairment of eNOS in endothelial cells infected with CMV, and that this is due to increased levels of ADMA, the competitive inhibitor of NOS.…”

Section: Impairment Of the Nitric Oxide Synthase Pathway In Cmv-inducmentioning

confidence: 92%

The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.

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“…11 HSV1 DNA has been found in some but not all samples of carotid atherosclerotic lesions. 12,13 The recurrent outbreaks associated with HSV infection and high population prevalence of exposure have made it an interesting target for epidemiological study.…”

Section: Herpesvirus Familymentioning

confidence: 99%

“…12,13 The recurrent outbreaks associated with HSV infection and high population prevalence of exposure have made it an interesting target for epidemiological study. 11 For CMV, evidence for involvement in vascular disease has been garnered from polymerase chain reaction (PCR) detection of CMV DNA in atherosclerotic lesions. For example, Hendrix et al found CMV DNA in 90% of advanced atherosclerotic lesions compared with only 50% of control patients with no or minimal atherosclerosis.…”

Section: Herpesvirus Familymentioning

confidence: 99%

‘Infectious Burden’ - New Insights into Stroke Prevention

Luna¹,

Elkind²

2010

European Neurological Review

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Atherosclerosis is a complex inflammatory disease process of the arterial vessels.1 Chronic and acute infections have been implicated as risk factors that increase the risk of stroke, myocardial infarction (MI) and other vascular events. However, no single pathogen is likely to be responsible for elevated vascular risk. Pathogens as Risk Factors for Atherosclerosis Chlamydia pneumoniaeChlamydia pneumoniae is a common respiratory pathogen believed to be responsible for approximately 10% of non-hospital-acquired pneumonias. 3 C. pneumoniae is one of the best-studied organisms believed to be associated with cardiovascular disease. Studies that have evaluated human samples of atherosclerotic lesions using electron microscopy, molecular DNA methods and immunostaining techniques have identified C. pneumoniae in coronary, carotid, aortic and popliteal plaque. 4 The majority of these studies have identified pathogen DNA or antigen only; however, a few studies have isolated viable C. pneumoniae organisms. 5,6 C. pneumoniae has been identified in both early-and late-stage fibrous plaque and, in particular, in carotid and cerebral arterial vessels. 7-9Herpesvirus FamilyHerpesviruses were initially identified as potential causes of atherosclerosis in animal models, and they have been the target of investigations into the association of infectious agents and atherosclerosis since then. 10 The most thoroughly investigated of the eight herpesvirus known to commonly infect humans are herpes simplex virus 1 (HSV1), HSV2 and cytomegalovirus (CMV). HSV1infection has been associated with accelerated atheroma formation in apolipoprotein E -/-(apoE -/-) mice, with a reduction in progression when treated with antiviral therapies. 11 HSV1 DNA has been found in some but not all samples of carotid atherosclerotic lesions. 12,13 The recurrent outbreaks associated with HSV infection and high population prevalence of exposure have made it an interesting target for epidemiological study. 'Infectious Burden' -New Insights into Stroke PreventionBrain Trauma Stroke AbstractChronic and acute infections have been implicated as risk factors that increase the risk of stroke, myocardial infarction (MI) and other vascular events. The lack of consistency among studies attempting to link exposure to infectious pathogens and stroke risk provides empirical evidence that a single pathogen is likely not responsible for stroke. Reconsidering exposure as an 'infectious burden' (IB) aligns with our understanding that the totality of pro-inflammatory agents can contribute to atherosclerosis and vascular risk. We define IB as the cumulative life-course exposure to infectious agents that elicit strong inflammatory responses and review the varied approaches to operationalising this measure.There is promising research investigating the role of acute and chronic IB suggesting that there may be a causal role of pathogens in atherosclerotic progression and plaque destabilisation to negatively affect vascular risk; however, the evidence is preliminary.

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Herpesvirus Infection Accelerates Atherosclerosis in the Apolipoprotein E–Deficient Mouse

Cited by 96 publications

References 39 publications

Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice

Transgenic human C-reactive protein is not proatherogenic in apolipoprotein E-deficient mice

The Role of Viruses in Cardiac Allograft Vasculopathy

‘Infectious Burden’ - New Insights into Stroke Prevention

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