Increased Thrombosis After Arterial Injury in Human C-Reactive Protein–Transgenic Mice

Danenberg, Haim; Szalai, Alexander J.; Swaminathan, Rajesh V.; Lin, Peng; Chen, Zhiping; Seifert, Philip; Fay, William P.; Simon, Daniel I.; Edelman, Elazer R.

doi:10.1161/01.cir.0000085568.13915.1e

Cited by 260 publications

(199 citation statements)

References 25 publications

(21 reference statements)

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“…Wild-type and CRPtg mice not treated with aspirin or heparin bolus had occlusion rates of 15% and 75%, respectively (data not shown), as reported earlier [3]. When mice were treated with aspirin, neointimal formation after guide-wire injury of the femoral artery was less profound in CRPtg compared to wild-type mice ( Fig.…”

Section: Arterial Response To Injurysupporting

confidence: 84%

“…To prevent thrombosis [3], aspirin treatment was started on the day prior to surgery (5 mg/kg, i.p. daily until artery harvest).…”

Section: Wire Injury Modelmentioning

confidence: 99%

“…CRP levels are associated with future cardiovascular events in seemingly healthy subjects and with worse prognosis in acute coronary patients [1]. CRP promotes thrombosis [2,3] and complement activation [4], and might impact lipoprotein metabolism [5]. The confluence of clinical and basic evidence suggests that CRP should predict outcome after vascular intervention.…”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown, using a human CRP transgenic mouse (CRPtg) model, that human CRP accelerates thrombosis [3] induced by guide-wire denudation of the femoral artery or by carotid photochemical injury. The current study examined whether CRP affects neointima formation in the context of PCI independent of its ability to induce thrombosis.…”

Section: Introductionmentioning

confidence: 99%

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Neointimal formation is reduced after arterial injury in human crp transgenic mice

et al. 2008

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Objectives/Methods-Elevated CRP levels predict increased incidence of cardiovascular events and poor outcomes following interventions. There is the suggestion that CRP is also a mediator of vascular injury. Transgenic mice carrying the human CRP gene (CRPtg) are predisposed to arterial thrombosis post-injury. We examined whether CRP similarly modulates the proliferative and hyperplastic phases of vascular repair in CRPtg when thrombosis is controlled with daily aspirin and heparin at the time of trans-femoral arterial wire-injury.Results-Complete thrombotic arterial occlusion at 28 days was comparable for wild-type and CRPtg mice (14 and 19%, respectively). Neointimal area at 28d was 2.5 fold lower in CRPtg (4190 ± 3134 μm 2 , n = 12) compared to wild-types (10,157 ± 8890 μm 2 , n = 11, p < 0.05). Likewise, neointimal/media area ratio was 1.10 ± 0.87 in wild-types and 0.45 ± 0.24 in CRPtg (p < 0.05). Seven days post-injury, cellular proliferation and apoptotic cell number in the intima were both less pronounced in CRPtg than wild-type. No differences were seen in leukocyte infiltration or endothelial coverage. CRPtg mice had significantly reduced p38 MAPK signaling pathway activation following injury.Conclusions-The pro-thrombotic phenotype of CRPtg mice was suppressed by aspirin/ heparin, revealing CRP's influence on neointimal growth after trans-femoral arterial wire-injury. Signaling pathway activation, cellular proliferation, and neointimal formation were all reduced in CRPtg following vascular injury. Increasingly we are aware of CRP multipotent effects. Once considered only a risk factor, and recently a harmful agent, CRP is a far more complex regulator of vascular biology.

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Section: Arterial Response To Injurysupporting

confidence: 84%

“…To prevent thrombosis [3], aspirin treatment was started on the day prior to surgery (5 mg/kg, i.p. daily until artery harvest).…”

Section: Wire Injury Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Neointimal formation is reduced after arterial injury in human crp transgenic mice

et al. 2008

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“…The infiltrating inflammatory cells release mediators that modulate smooth muscle cell migration and proliferation as well as further inflammation [1,2]. Elevated inflammatory markers such as total leukocyte count [3,4] and C-reactive protein levels [5,6] are associated with worse outcome after percutaneous coronary artery interventions (PCI). Suppression of innate immunity by various strategies alleviates the inflammatory response following injury and suppresses excessive reactivity, as evidenced by lesser degree of neointimal formation [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Innate immunity has a dual effect on vascular healing: Suppression and aggravation of neointimal formation and remodeling post-endotoxin challenge

et al. 2008

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Background-Inflammation is important to vascular repair following injury, modulating neointimal proliferation and remodeling. Previously, we have shown that a low-intensity inflammatory response aggravates neointimal formation following balloon and stent injury. The present study examined whether modulation of the extent and timing of nonspecific inflammation mediates the local vascular response in an additive unidirectional or rather a bidirectional fashion.Methods and results-Rabbits subjected to denudation and balloon injury of the iliac artery were treated with low(1 µg/kg) or high (100µg/kg) doses of bacterial endotoxin (LPS) immediately after injury, or with early high-dose LPS administered 3 days prior to injury (preconditioning). Neointimal formation at 28 days was significantly increased in the low-dose group (0.537 ± 0.059mm 2 ) as compared with controls (0.3 ± 0.03mm 2 ). High-dose LPS did not significantly affect neointimal formation while early high dose significantly reduced neointima (0.296 ± 0.033 and 0.194 ± 0.025mm 2 , respectively, n = 12-14/group). Arterial wall and systemically circulating interleukin-1β levels, and monocyte CD14 activation correlated with neointimal formation. Vascular remodeling was accelerated in animals treated with low-or high-dose LPS while not affected in the preconditioned group. Remodeling index inversely correlated with arterial matrix metalloproteinase-2 levels 6 days after injury.Conclusions-The extent and timing of nonspecific inflammation that is concurrent with vascular injury can determine different and opposite vascular repair patterns.

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Association of Polymorphisms in the CRP Gene With Circulating C-Reactive Protein Levels and Cardiovascular Events

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et al. 2006

JAMA

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Increased Thrombosis After Arterial Injury in Human C-Reactive Protein–Transgenic Mice

Cited by 260 publications

References 25 publications

Neointimal formation is reduced after arterial injury in human crp transgenic mice

Neointimal formation is reduced after arterial injury in human crp transgenic mice

Innate immunity has a dual effect on vascular healing: Suppression and aggravation of neointimal formation and remodeling post-endotoxin challenge

Association of Polymorphisms in the CRP Gene With Circulating C-Reactive Protein Levels and Cardiovascular Events

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