Macrophages in Vascular Inflammation: Origins and Functions.

Macrophages influence various processes of cardiovascular inflammation. Whether they are of embryonic or post-natal hematopoietic origin, their balance in differential activation may direct the course of inflammation. Accelerated macrophage activation and accumulation through a pro-inflammatory signaling pathway may result in extensive tissue damage, adverse repair, and worsened clinical outcomes. Attenuation of such a mechanism and/or promotion of the anti-inflammatory macrophage activation may lead to early resolution of inflammation. Elucidating multiple novel mechanisms of monocyte and macrophage activation leads to a better understanding of their roles in vascular inflammation. In turn, this begets better therapeutic target identification and biomarker discovery. Combined with increasingly sensitive and specific imaging techniques, we continue to push back early detection and monitoring to provide us with a greater window for disease modification. The potential success of cytokine-targeted therapy will be solid proof of the inflammatory hypothesis of atherothrombosis.

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

BACKGROUND New pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPARα (peroxisome proliferator-activated receptor α) 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 × 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] mm3 versus control, 54.2 [41.2-81.1] mm3; P=0.03). In addition, pemafibrate suppressed day 28 stent-induced cellular inflammation and neointima expression of the inflammatory mediators TNF-α (tumor necrosis factor-α) 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.

Successful Coronary Flow Restoration by Stent-Free Strategy Using the Pull-Back Method of Cutting Balloon in Spontaneous Coronary Artery Dissection.

This report describes a 46-year-old woman with ST-elevation myocardial infarction due to spontaneous coronary artery dissection. Because continuous chest pain and ST-segment elevation in electrocardiography indicated ongoing cardiac ischemia, the urgent revascularization strategy was used using a novel method of cutting balloon angioplasty, "the pull-back of inflated cutting balloon," which led to the successful coronary flow restoration and complete healing of dissected coronary artery in 1 year. The pull-back of the inflated cutting balloon method is a useful therapeutic option in the treatment of patients with spontaneous coronary artery dissection with ongoing cardiac ischemia.

Le présent rapport décrit le cas d'une femme de 46 ans ayant subi un infarctus du myocarde avec élévation du segment ST dû à une dissection spontanée de l'artère coronaire (DSAC). Compte tenu de la douleur thoracique continue et de l'élévation du segment ST à l'électrocardiographie, signes indicateurs d'une ischémie cardiaque en cours, une revascularisation d'urgence a été employée à l'aide d'une nouvelle méthode d'angioplastie au ballon coupant. « La traction du ballon coupant gonflé ¼ a permis en l'espace d'un an de restaurer avec succès le débit coronarien et d'obtenir une cicatrisation complète de l'artère ayant subi la déchirure. La méthode de traction du ballon coupant gonflé s'avère une option thérapeutique utile dans le traitement des patients présentant une DSAC associée à des symptômes d'ischémie cardiaque.

PARP9 and PARP14 cross-regulate macrophage activation via STAT1 ADP-ribosylation.

Despite the global impact of macrophage activation in vascular disease, the underlying mechanisms remain obscure. Here we show, with global proteomic analysis of macrophage cell lines treated with either IFNγ or IL-4, that PARP9 and PARP14 regulate macrophage activation. In primary macrophages, PARP9 and PARP14 have opposing roles in macrophage activation. PARP14 silencing induces pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells, whereas it suppresses anti-inflammatory gene expression and STAT6 phosphorylation in M(IL-4) cells. PARP9 silencing suppresses pro-inflammatory genes and STAT1 phosphorylation in M(IFNγ) cells. PARP14 induces ADP-ribosylation of STAT1, which is suppressed by PARP9. Mutations at these ADP-ribosylation sites lead to increased phosphorylation. Network analysis links PARP9-PARP14 with human coronary artery disease. PARP14 deficiency in haematopoietic cells accelerates the development and inflammatory burden of acute and chronic arterial lesions in mice. These findings suggest that PARP9 and PARP14 cross-regulate macrophage activation.