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Oral Resolvin D1 attenuates early inflammation but not intimal hyperplasia in a rat carotid angioplasty model.

ABSTRACT: 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.

SUBMITTER: Mottola G

PROVIDER: S-EPMC7265259 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Oral Resolvin D1 attenuates early inflammation but not intimal hyperplasia in a rat carotid angioplasty model.

Mottola Giorgio G Werlin Evan C EC Wu Bian B Chen Mian M Chatterjee Anuran A Schaller Melinda S MS Conte Michael S MS

Prostaglandins & other lipid mediators 20191210

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 t ...[more]

PMID: 31841663

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Project description:ObjectiveLipid mediators derived from omega-3 polyunsaturated fatty acids such as resolvin D1 (RvD1) accelerate the resolution of inflammation and have potential as vascular therapeutics. The objective of this study was to evaluate local perivascular delivery of RvD1 as a means to attenuate neointimal hyperplasia in a rat model of arterial injury.MethodsSmooth muscle cells were harvested from rat aortas to study the effects of RvD1 on rat arterial vascular smooth muscle cell responses in vitro, with focus on inflammation, proliferation, migration, cytoskeletal changes, and cytotoxicity. The safety and efficacy of perivascular delivery of RvD1 through thin biodegradable three-layered poly(lactic-co-glycolic acid) wraps or 25% Pluronic F127 gels were studied in a rat model of carotid angioplasty. A total of 200 ng of RvD1 was loaded into each construct for perivascular delivery after injury. Morphometric and histologic analyses were performed 3 and 14 days after injury.ResultsRvD1 attenuated rat arterial vascular smooth muscle cell inflammatory pathways, proliferation, migration, and mitogen-induced cytoskeletal changes in vitro, without evidence of cytotoxicity. RvD1-loaded wraps reduced neointimal formation after carotid angioplasty by 59% vs no-wrap controls (P = .001) and by 45% vs vehicle-wrap controls (P = .002). RvD1-loaded Pluronic gels similarly reduced neointimal formation by 49% vs no-gel controls (P = .02) and by 52% vs vehicle-gel controls (P = .02). No group was associated with infection, thrombosis, or negative vessel remodeling. Wraps were found to be easier to apply than gel constructs. Ki67 proliferation index was significantly lower in RvD1-loaded wrap-treated arteries compared with both no-wrap and vehicle-wrap controls at both 3 and 14 days after injury (65% vs no-wrap group and 70% vs vehicle-wrap group at day 3, 49% vs both control groups at day 14; P < .05). Similarly, oxidative stress (30% and 29%; P < .05) and nuclear factor κB activation (42% and 45%; P < .05) were significantly lower in the RvD1-loaded wrap group compared with both no-wrap and vehicle-wrap controls at 3 days after injury.ConclusionsLocal perivascular delivery of RvD1 attenuates formation of neointimal hyperplasia without associated toxicity in a rat model of carotid angioplasty. This effect is likely due to attenuation of inflammatory pathways as well as decreased arterial smooth muscle cell proliferation and migration.

Project description:BackgroundDiabetes exacerbates abnormal vascular smooth muscle cell (VSMC) accumulation in response to arterial wall injury. Vinpocetine has been shown to improve vascular remolding; however, little is known about the direct effects of vinpocetine on vascular complications mediated by diabetes. The objective of this study was to determine the effects of vinpocetine on hyperglycemia-facilitated neointimal hyperplasia and explore its possible mechanism.Materials and methodsNondiabetic and diabetic rats were subjected to balloon injury of the carotid artery followed by 3-week treatment with either vinpocetine (10 mg/kg/day) or saline. Morphological analysis and proliferating cell nuclear antigen (PCNA) immunostaining were performed on day 21. Rat VSMCs proliferation was determined with 5-ethynyl-20-deoxyuridine cell proliferation assays. Chemokinesis was monitored with scratch assays, and production of reactive oxygen species (ROS) was assessed using a 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) flow cytometric assay. Apoptosis was detected by annexin V-FITC/PI flow cytometric assay. Cell signaling was assessed by immunblotting.ResultsVinpocetine prevented intimal hyperplasia in carotid arteries in both normal (I/M ratio: 93.83 ± 26.45% versus 143.2 ± 38.18%, P<0.05) and diabetic animals (I/M ratio: 120.5 ± 42.55% versus 233.46 ± 33.98%, P<0.05) when compared to saline. The in vitro study demonstrated that vinpocetine significantly inhibited VSMCs proliferation and chemokinesis as well as ROS generation and apoptotic resistance, which was induced by high glucose (HG) treatment. Vinpocetine significantly abolished HG-induced phosphorylation of Akt and JNK1/2 without affecting their total levels. For downstream targets, HG-induced phosphorylation of I?B? was significantly inhibited by vinpocetine. Vinpocetine also attenuated HG-enhanced expression of PCNA, cyclin D1 and Bcl-2.ConclusionsVinpocetine attenuated neointimal formation in diabetic rats and inhibited HG-induced VSMCs proliferation, chemokinesis and apoptotic resistance by preventing ROS activation and affecting MAPK, PI3K/Akt, and NF-?B signaling.

Dataset Information

Oral Resolvin D1 attenuates early inflammation but not intimal hyperplasia in a rat carotid angioplasty model.

Publications

Oral Resolvin D1 attenuates early inflammation but not intimal hyperplasia in a rat carotid angioplasty model.

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