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This study was supported by research grants from Kowa Company, Ltd, Nagoya, Japan, to Masanori Aikawa and Farouc A. Jaffer, the National Institutes of Health (R01HL126901 and R01HL149302 to Masanori Aikawa; R01HL122388, R01HL137913, and R01HL150538 to Farouc A. Jaffer; K08HL130465 to Eric A. Osborn; R01HL136431 and R01HL147095 to Elena Aikawa; and R01HL080472 to Peter Libby), American Heart Association (18CSA34080399 to Peter Libby), and the RRM Charitable Fund to Peter Libby. The near--infrared fluorescence--optical coherence tomography system was developed in part under R01HL093717 to Guillermo J. Tearney. Kowa Company, Ltd, Nagoya, Japan, provided partial research funding support for this study but was not involved in the study design or data analysis.

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Highly Selective PPARα (Peroxisome Proliferator-Activated Receptor α) Agonist Pemafibrate Inhibits Stent Inflammation and Restenosis Assessed by Multimodality Molecular-Microstructural Imaging

Publicado en:Journal Of The American Heart Association. 10 (20): e020834- - 2021-10-19 10(20), DOI: 10.1161/jaha.121.020834

Autores: Iwata, Hiroshi; Osborn, Eric A; Ughi, Giovanni J; Murakami, Kentaro; Goettsch, Claudia; Hutcheson, Joshua D; Mauskapf, Adam; Mattson, Peter C; Libby, Peter; Singh, Sasha A; Matamalas, Joan; Aikawa, Elena; Tearney, Guillermo J; Aikawa, Masanori; Jaffer, Farouc A

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BACKGROUND New pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPAR alpha (peroxisome proliferator-activated receptor alpha) agonist, suppresses coronary stent-induced arterial inflammation and neointimal hyperplasia. METHODS AND RESULTS Yorkshire pigs randomly received either oral pemafibrate (30 mg/day; n=6) or control vehicle (n=7) for 7 days, followed by coronary arterial implantation of 3.5 x 12 mm bare metal stents (2-4 per animal; 44 stents total). On day 7, intracoronary molecular-structural near-infrared fluorescence and optical coherence tomography imaging was performed to assess the arterial inflammatory response, demonstrating that pemafibrate reduced stent-induced inflammatory protease activity (near-infrared fluorescence target-to-background ratio: pemafibrate, median [25th-75th percentile]: 2.8 [2.5-3.3] versus control, 4.1 [3.3-4.3], P=0.02). At day 28, animals underwent repeat near-infrared fluorescence-optical coherence tomography imaging and were euthanized, and coronary stent tissue molecular and histological analyses. Day 28 optical coherence tomography imaging showed that pemafibrate significantly reduced stent neointima volume (pemafibrate, 43.1 [33.7-54.1] mm(3) versus control, 54.2 [41.2-81.1] mm(3); P=0.03). In addition, pemafibrate suppressed day 28 stent-induced cellular inflammation and neointima expression of the inflammatory mediators TNF-alpha (tumor necrosis factor-alpha) and MMP-9 (matrix metalloproteinase 9) and enhanced the smooth muscle differentiation markers calponin and smoothelin. In vitro assays indicated that the STAT3 (signal transducer and activator of transcription 3)-myocardin axes mediated the inhibitory effects of pemafibrate on smooth muscle cell proliferation. CONCLUSIONS Pemafibrate reduces preclinical coronary stent inflammation and neointimal hyperplasia following bare metal stent deployment. These results motivate further trials evaluating pemafibrate as a new strategy to prevent clinical stent restenosis.

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