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Dietary Zyflamend Inhibits Intimal Hyperplasia Development via the Attenuation of Macrophage Infiltration in a Rodent Model of Vascular Injury
Michael R Buckley1, Deidra J Mountain1, Lindsay M Bools1, Stacy S Kirkpatrick1, Jay Whelan2, Paul Terry3, Michael B Freeman1, Oscar H Grandas1
1University of Tennessee Graduate School of Medicine, Knoxville, TN;2University of Tennessee Department of Nutrition, Knoxville, TN;3University of Tennessee Department of Public Health, Knoxville, TN

Introduction: Zyflamend is a poly-herbal dietary supplement that has been previously shown to have potent anti-inflammatory properties, inhibit cell proliferation, and attenuate inflammatory-modulated pathologies. Intimal hyperplasia (IH), the characteristic response of a vessel to injury, is thought to be heavily regulated by an immune-mediated reaction. Phenotypic modification of medial vascular smooth muscle cells (VSMC) and their intimal migration are the basis of lesion formation. More recently evidence has shown that monocyte/macrophage infiltration is an independent predictor of restenosis and can contribute to IH development by serving as precursors to neointimal myofibroblasts. Here we examined the effect of Zyflamend on inflammatory-dependent vascular remodeling mechanisms and in the prevention of IH in an animal model of vascular injury.
Methods: The diets of aged male rats were supplemented with human equivalent doses of Zyflamend or placebo for 7d prior to balloon angioplasty-induced injury of the right carotid artery and continuously thereafter. Serum was collected pre- and post-supplementation and at sacrifice for cytokine analysis via qualitative and quantitative multiplex array. Carotid tissue was collected 28d post-injury, stained with trichrome elastin for intima:media (I:M) quantification, and with isoform-specific antibodies for matrix metalloproteinase (MMP) remodeling enzymes, proliferating cellular nuclear antigen (PCNA), and macrophage scavenger receptor (MSR).
Results: I:M was decreased in Zyflamend animals compared to placebo (0.43±0.14 vs. 0.82±0.12, n=10, P<0.05; Fig1A). Cytokine screening indicated injury-induced interleukin family isoforms, interferon-γ, and macrophage inflammatory proteins were downregulated by Zyflamend supplementation (Fig1B). While MMPs and PCNA were not affected, the presence of MSR was significantly downregulated in the tissue of Zyflamend animals compared to placebo controls (8.5±0.7% vs. 3.9±0.6%, n=5, P<0.01; Fig1C)
Conclusion: Dietary supplementation with Zyflamend inhibits IH development in vivo. This inhibition occurs independent of matrix remodeling mechanisms and without controlling cellular proliferation. Zyflamend supplementation does attenuate the acute inflammatory response following injury and results in decreased MSR expression in the injured vessel wall. Ongoing studies are evaluating the role of decreased macrophage infiltration and myofibroblast differentiation as a possible mechanism for Zyflamend controlling IH. Determining a mechanism of protection is necessary to warrant future clinical investigations of Zyflamend as a therapeutic anti-inflammatory agent in the prevention of vascular disease progression.


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