Systemic application of sirolimus prevents neointima formation not via a direct anti-proliferative effect but via its anti-inflammatory properties

INTERNATIONAL JOURNAL OF CARDIOLOGY

卷:238

Article

Daniel, Jan-Marcus¹  Dutzmanna, Jochen¹  Brunsch, Hannes¹  Bauersachs, Johann¹  Braun-Dullaeus, Rdiger²  Sedding, Daniel G.¹ 

[1] Hannover Med Sch, Dept Cardiol & Angiol, Hannover, Germany

[2] Otto von Guericke Univ, Dept Cardiol Angiol & Pneumol, Magdeburg, Germany

关键词: Neointima formation;    Sirolimus;    Re-endothelialization;    Inflammation;    Smooth muscle cells;    Progenitor cells;   

DOI  :  10.1016/j.ijcard.2017.03.052

来源: Elsevier

【 摘 要 】

Background: Systemic treatmentwith sirolimus, as used for immunosuppression in transplant patients, results in markedly low rates of in-stent restenosis. Since the underlying mechanisms remain obscure, we aimed to determine the molecular and cellular effects of systemic sirolimus treatment on vascular remodeling processes. Methods and results: Systemic sirolimus treatment significantly reduced smooth muscle cell (SMC) proliferation 14 days after wire-induced injury and neointima formation 28 days after injury in C57BL/6 mice, while simultaneously impairing re-endothelialization. Interestingly, in vitro, sirolimus had no direct effect on the proliferation of SMC or endothelial cells (EC) at serum concentrations observed after systemic application. In contrast, sirolimus reduced the adhesion of leukocytes (CD45(+)) and bone marrow-derived progenitor cells (CD34(+)) to activated EC by down-regulating the adhesion molecules ICAM-1 and VCAM-1. In addition, sirolimus treatment also significantly reduced the upregulation of ICAM-1 and VCAM-1 and the recruitment of monocytic cells (MOMA-2(+)) in neointimal lesions in vivo. Conclusion: Our findings show that systemic sirolimus treatment effectively prevents SMC and EC proliferation in vivo without directly affecting these cells. Instead, sirolimus prevents neointima formation and re-endothelialization by attenuating the inflammatory response after injury with secondary effects on SMC and EC proliferation. Thus, despite a similar net effect, the mechanisms of systemic sirolimus treatment are largely different from the local effects achieved after application of sirolimus-eluting stents. (C) 2017 The Authors. Published by Elsevier Ireland Ltd.

【 授权许可】

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