Department of Surgery, Division of Vascular and Endovascular Surgery, University of California San Francisco, Cardiovascular Research Institute, 555 Mission Bay Blvd South, San Francisco, 94143, CA, USA.
Department of Surgery, Division of Vascular and Endovascular Surgery, University of California San Francisco, Cardiovascular Research Institute, 555 Mission Bay Blvd South, San Francisco, 94143, CA, USA.
Prostaglandins Other Lipid Mediat. 2020 Feb;146:106401. doi: 10.1016/j.prostaglandins.2019.106401. Epub 2019 Dec 10.
Inflammation ensuing from vascular injury promotes intimal hyperplasia (IH) and restenosis. Resolvin D1 (RvD1) is a lipid mediator that attenuates IH in vivo when delivered locally to the vessel wall in animal models. We tested the hypothesis that peri-procedural oral administration of RvD1 could blunt the local inflammatory response to angioplasty, and attenuate downstream IH. Carotid angioplasty was performed on rats fed with either RvD1 or vehicle through oral gavage, starting one day prior to injury until post-operative day (POD) 3 or 14 when arteries were harvested. To study pharmacokinetics and bioactivity of oral RvD1, we measured plasma RvD1 by ELISA, whole blood phagocytosis activity using flow cytometry, and cAMP levels in the thoracic aorta by ELISA. Carotid arteries were harvested on POD3 for staining (anti-CD45, anti-Myeloperoxidase (MPO), anti-Ki67 or dihydroethidium (DHE) for reactive oxygen species), mRNA expression of target genes (quantitative RT-PCR), or on POD14 for morphometry (elastin stain). RvD1 plasma concentration peaked 3 h after gavage in rats, at which point we concurrently observed an increase in circulating monocyte phagocytosis activity and aortic cAMP levels in RvD1-treated rats vs. vehicle. Oral RvD1 attenuated local arterial inflammation after angioplasty by reducing CD45+, MPO+, Ki67+ cells, and DHE staining intensity. Oral RvD1 also reduced the expression of several pro-inflammatory genes within the injured vessels. However, oral RvD1 did not significantly reduce IH. Oral RvD1 attenuated acute inflammation within the arterial wall after angioplasty in rats, but did not significantly affect IH.
血管损伤引起的炎症促进内膜增生 (IH) 和再狭窄。解析素 D1 (RvD1) 是一种脂质介质，当在动物模型中局部递送至血管壁时，可减轻体内 IH。我们检验了这样一个假设，即在血管成形术前口服给予 RvD1 可以减轻血管成形术引起的局部炎症反应，并减轻下游的 IH。通过口服灌胃，将 RvD1 或载体给予喂养的大鼠进行颈动脉血管成形术，从损伤前一天开始给药，直到术后第 3 天或 14 天取动脉。为了研究口服 RvD1 的药代动力学和生物活性，我们通过 ELISA 测量了血浆中的 RvD1，通过流式细胞术测量了全血吞噬活性，通过 ELISA 测量了胸主动脉中的 cAMP 水平。在术后第 3 天取颈动脉进行染色（抗 CD45、抗髓过氧化物酶 (MPO)、抗 Ki67 或二氢乙啶 (DHE) 用于检测活性氧）、靶基因的 mRNA 表达（定量 RT-PCR），或在术后第 14 天取颈动脉进行形态计量学（弹力蛋白染色）。RvD1 在大鼠灌胃后 3 小时达到血浆浓度峰值，此时我们同时观察到 RvD1 治疗组大鼠的循环单核细胞吞噬活性和主动脉 cAMP 水平增加。与载体相比，口服 RvD1 减轻了血管成形术后局部动脉炎症，减少了 CD45+、MPO+、Ki67+细胞和 DHE 染色强度。口服 RvD1 还降低了损伤血管内的几个促炎基因的表达。然而，口服 RvD1 并没有显著减少 IH。口服 RvD1 减轻了大鼠血管成形术后动脉壁内的急性炎症，但对 IH 没有明显影响。
