Abstract
Atherosclerosis is a chronic inflammatory disease, whose progression and stability are modulated, among other factors, by an innate and adaptive immune response. Prodiginines are bacterial secondary metabolites with antiproliferative and immunomodulatory activities; however, their effect on the progression or vulnerability of atheromatous plaque has not been evaluated. This study assessed the therapeutic potential of prodigiosin and undecylprodigiosin on inflammatory marker expression and atherosclerosis. An in vitro and in vivo study was carried out. Migration, low-density lipoprotein (LDL) uptake and angiogenesis assays were performed on cell types involved in the pathophysiology of atherosclerosis. In addition, male LDL receptor null (Ldlr-/-) C57BL/6J mice were treated with prodigiosin or undecylprodigiosin for 28 days. Morphometric analysis of atherosclerotic plaques, gene expression of atherogenic factors in the aortic sinus and serum cytokine quantification were performed. The treatments applied had slight effects on the in vitro tests performed, highlighting the inhibitory effect on the migration of SMCs (smooth muscle cells). On the other hand, although no significant difference in atherosclerotic plaque progression was observed, gene expression of IL-4 and chemokine (C-C motif) ligand 2 (Ccl2) was downregulated. In addition, 50 µg/Kg/day of both treatments was sufficient to inhibit circulating tumor necrosis factor alpha (TNF-α), interleukin-2 (IL-2) and interferon-gamma (IFN-γ) in serum. These results suggested that prodigiosin and undecylprodigiosin modulated inflammatory markers and could have an impact in reducing atherosclerotic plaque vulnerability.
Highlights
Atherosclerosis is the pathophysiological process that underlies the development of the main cardiovascular diseases and is the leading cause of death in industrialized countries [1]
There is considerable evidence suggesting that atherosclerosis is more than just a lipid disorder, and an inflammatory process involving the recruitment of many different cell types, including endothelial and smooth muscle cells, monocyte-derived macrophages and T lymphocytes [2]
PG does not affect the production of IL-2, which would not affect the expansion of atheroprotective Tregs [22]. These findings suggest that PG could exert an immunomodulatory effect on T cells, which in turn might contribute to modifying the progression of atherosclerotic plaques
Summary
Atherosclerosis is the pathophysiological process that underlies the development of the main cardiovascular diseases and is the leading cause of death in industrialized countries [1]. These findings suggest that PG could exert an immunomodulatory effect on T cells, which in turn might contribute to modifying the progression of atherosclerotic plaques To test this hypothesis, the in vitro effect of these compounds on key processes in endothelial cells, smooth muscle and macrophages, three of the main cellular phenotypes involved in the pathophysiology of atherosclerosis, was evaluated. To evaluate possible effects on atherogenesis, inflammation and immune response, an in vivo trial was designed in C57bl/6 Ldlr-/- mice, which were induced with advanced atherosclerotic lesions before starting the respective treatments The choice of this animal model was based on the need for a functional APOE protein, given the importance of this protein in modulating various inflammatory processes involved in atherogenesis [23]. UPG on inflammatory markers in cells involved with atherosclerosis, and their impact on aItnht.eJr. oMsocl.leSrcoi.t2i0c20p,l2a1q, 6u4e17vulnerability
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