Delayed therapy with clopidogrel and everolimus prevents progression of transplant arteriosclerosis and impairs humoral alloimmunity in murine aortic allografts

Heim, Christian; Eckl, S.; Preidl, Raimund; Ramsperger-Gleixner, M.; Koch, N.; Goldmann, K; Spriewald, Bernd M.; Weyand, Michael; Ensminger, Stephan

doi:10.1093/ejcts/ezu098

Cited by 23 publications

(12 citation statements)

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“…However, a delayed anti-platelet therapy, when atherosclerotic lesions are already present, was only able to ameliorate the process of plaque formation to a certain extent, but did not result in significant reverse remodelling within the vascular wall. These findings are in contrast to the results from a murine aortic transplant model, where the progress of intima proliferation is significantly reduced even when vascular lesions were already present [28]. We would speculate at this stage that the time point of delayed clopidogrel administration in this study may have been too late to reach significant levels of progress reduction.…”

Section: Discussioncontrasting

confidence: 99%

Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo

et al. 2015

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The anti-platelet drug clopidogrel has been shown to modulate adhesion molecule and cytokine expression, both playing an important role in the pathogenesis of atherosclerosis. The aim of this study was to investigate the impact of clopidogrel on the development and progression of atherosclerosis. ApoE(-/-) mice fed an atherogenic diet (cholesterol: 1 %) for 6 months received a daily dose of clopidogrel (1 mg/kg) by i.p. injection. Anti-platelet treatment was started immediately in one experimental group, and in another group clopidogrel was started 2 month after beginning of the atherogenic diet. Blood was analysed at days 30, 60 and 120 to monitor the lipid profile. After 6 months the aortic arch and brachiocephalic artery were analysed by Sudan IV staining for plaque size and by morphometry for luminal occlusion. Serum levels of various adhesion molecules were investigated by ELISA and the cellular infiltrate was analysed by immunofluorescence. After daily treatment with 1 mg/kg clopidogrel mice showed a significant reduction of atherosclerotic lesions in the thoracic aorta and within cross sections of the aortic arch [plaque formation 55.2 % (clopidogrel/start) vs. 76.5 % (untreated control) n = 8, P < 0.05]. After treatment with clopidogrel P-/E-selectin levels and cytokine levels of MCP-1 and PDGFβ were significantly reduced as compared to controls. The cellular infiltrate showed significantly reduced macrophage and T-cell infiltration in clopidogrel-treated animals. These results show that clopidogrel can effectively delay the development and progression of 'de-novo' atherosclerosis. However, once atherosclerotic lesions were already present, anti-platelet treatment alone did not result in reverse remodelling of these lesions.

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Section: Discussioncontrasting

confidence: 99%

Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo

et al. 2015

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“…It has been shown that monotherapy with clopidogrel can effectively reduce the formation of transplant arteriosclerosis in a murine aortic allograft model . Furthermore, delayed treatment with clopidogrel and everolimus prevents the progression of transplant arteriosclerosis and impairs humoral immunity in murine aortic allografts . Ticlopidine showed profound suppression of platelet aggregation .…”

Section: Discussionmentioning

confidence: 99%

Early aspirin initiation following heart transplantation is associated with reduced risk of allograft vasculopathy during long‐term follow‐up

Peled

Lavee

Raichlin

et al. 2017

Clinical Transplantation

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“…38 For example, a report showed that a delayed anti-platelet therapy with clopidogrel and everolimus prevents progression of transplant arteriosclerosis in murine aortic allografts. 39 …”

Section: Discussionmentioning

confidence: 99%

Impaired Integrin β3 Delays Endothelial Cell Regeneration and Contributes to Arteriovenous Graft Failure in Mice

Liang

Wang

Liang

et al. 2015

ATVB

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Objective Neointima formation is associated with stenosis and subsequent thrombosis in arteriovenous grafts (AVG). A role of integrin β3 in the neointima formation of AVGs remains poorly understood. Approach and Results In integrin β3−/− mice, we found significantly accelerated occlusion of AVGs compared to the wild type mice. This is caused by the development of neointima and lack of endothelial regeneration. The latter is a direct consequence of impaired functions of circulating angiogenic cells (CACs) and platelets in integrin β3−/− mice. Evidence suggests the involvement of platelet regulating CAC homing to and differentiation at graft sites via TGF-β1 and Notch signaling pathway. First, CACs deficient of integrin β3 impaired adhesion activity toward exposed subendothelium. Second, platelets from integrin β3−/− mice failed to sufficiently stimulate CACs to differentiate into mature endothelial cells. Finally, we found that TGF-β1 level was increased in platelets from integrin β3−/− mice and resulted in enhanced Notch1 activation in CACs in AVGs. These results demonstrate that integrin β3 is critical for endothelial cell homing and differentiation. The increased TGF-β1 and Notch1 signaling mediates integrin β3−/−-induced AVG occlusion. This accelerated occlusion of AVGs was reversed in integrin β3−/− mice transplanted with the bone marrow from WT mice. Conclusion Our results suggest that boosting integrin β3 function in the endothelial cells and platelets could prevent neointima and thrombosis in AVGs.

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Delayed therapy with clopidogrel and everolimus prevents progression of transplant arteriosclerosis and impairs humoral alloimmunity in murine aortic allografts

Abstract: These results demonstrate that delayed treatment with clopidogrel and everolimus-representative of a clinical setting-prevents the progression of transplant arteriosclerosis and impairs humoral immunity in this experimental model.

Cited by 23 publications

References 24 publications

Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo

Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo

Early aspirin initiation following heart transplantation is associated with reduced risk of allograft vasculopathy during long‐term follow‐up

Impaired Integrin β3 Delays Endothelial Cell Regeneration and Contributes to Arteriovenous Graft Failure in Mice

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