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Visual Abstract, Highlights • This study shows that apoA-I may be an alternative strategy to improve the biocompatibility of stents. • Systemic infusions of apoA-I reduce in-stent neointimal hyperplasia in a murine model of stenting. • The cellular phenotype of the neointima post-stenting is altered by apoA-I infusions such that the smooth muscle cell phenotype is preserved, and there are fewer macrophages. • There was an increase in endothelial cell content of the arteries post-stenting in the mice infused with apoA-I, indicating an enhancement of endothelialization. • Systemic infusions of apoA-I inhibit platelet activation., Summary Even the most advanced drug-eluting stents evoke unresolved issues, including chronic inflammation, late thrombosis, and neoatherosclerosis. This highlights the need for novel strategies that improve stent biocompatibility. Our studies show that apolipoprotein A-I (apoA-I) reduces in-stent restenosis and platelet activation, and enhances endothelialization. These findings have therapeutic implications for improving stent biocompatibility.

Visual Abstract, Highlights • The atheroprotective effects of apoA-I are dependent on the plaque stage from which apoA-I is infused. • The atheroprotective effects of apoA-I infusions are also impaired in older mice with a greater disease milieu. • Ex vivo studies with mouse HDL found an impairment in HDL functionality with increasing disease/age of the mice as well as a reduced ability of apoA-I infusions to improve the atheroprotective functions of HDL. • Our study provides understanding regarding the disparity between the very positive results of HDL/apoA-I raising in preclinical studies, largely performed in younger animals with early-stage disease, and the large-scale HDL-raising clinical trials in more elderly patients with established plaque that have failed to show benefit., Summary Preclinical studies have shown benefit of apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL) raising in atherosclerosis; however, this has not yet translated into a successful clinical therapy. Our studies demonstrate that apoA-I raising is more effective at reducing early-stage atherosclerosis than late-stage disease, indicating that the timing of HDL raising is a critical factor in its atheroprotective effects. To date, HDL-raising clinical trials have only been performed in aged patients with advanced atherosclerotic disease. Our findings therefore provide insight, related to important temporal aspects of HDL raising, as to why the clinical trials have thus far been largely neutral.

Visual Abstract, Highlights • TSG-6 suppresses the development of atherosclerosis by decreasing inflammatory responses of endothelial cells and macrophages, endothelial proliferation, macrophage foam cell formation, and VSMC migration and proliferation. • TSG-6 also contributes to plaque stability by extracellular matrix production in the fibrous cap. • TSG-6 is expected to emerge as a new line of therapy against atherosclerosis and CAD. • This study also provides insights into the potential use of TSG-6 as a biomarker for CAD. • These findings may strengthen the clinical utility of TSG-6 in the diagnosis and treatment of CAD., Summary Tumor necrosis factor–stimulated gene-6 (TSG-6), an anti-inflammatory protein, was shown to be localized in the neointima of injury-induced rat arteries. However, the modulatory effect of TSG-6 on atherogenesis has not yet been reported. We aimed to evaluate the atheroprotective effects of TSG-6 on human endothelial cells (HECs), human monocyte-derived macrophages (HMDMs), human aortic smooth muscle cells (HASMCs) in vitro, and aortic lesions in apolipoprotein E–deficient mice, along with expression levels of TSG-6 in coronary lesions and plasma from patients with coronary artery disease (CAD). TSG-6 was abundantly expressed in HECs, HMDMs, and HASMCs in vitro. TSG-6 significantly suppressed cell proliferation and lipopolysaccharide-induced up-regulation of monocyte chemotactic protein-1, intercellular adhesion molecule-1, and vascular adhesion molecule-1 in HECs. TSG-6 significantly suppressed inflammatory M1 phenotype and suppressed oxidized low-density lipoprotein–induced foam cell formation associated with down-regulation of CD36 and acyl-CoA:cholesterol acyltransferase-1 in HMDMs. In HASMCs, TSG-6 significantly suppressed migration and proliferation, but increased collagen-1 and -3 expressions. Four-week infusion of TSG-6 into apolipoprotein E–deficient mice significantly retarded the development of aortic atherosclerotic lesions with decreased vascular inflammation, monocyte/macrophage, and SMC contents and increased collagen fibers. In addition, it decreased peritoneal M1 macrophages with down-regulation of inflammatory molecules and lowered plasma total cholesterol levels. In patients with CAD, plasma TSG-6 levels were significantly increased, and TSG-6 was highly expressed in the fibrous cap within coronary atherosclerotic plaques. These results suggest that TSG-6 contributes to the prevention and stability of atherosclerotic plaques. Thus, TSG-6 may serve as a novel therapeutic target for CAD.

The anti-atherogenic cytokine, TGF-β, plays a key role during macrophage foam cell formation by modulating the expression of key genes involved in the control of cholesterol homeostasis. Unfortunately, the molecular mechanisms underlying these actions of TGF-β remain poorly understood. In this study we examine the effect of TGF-β on macrophage cholesterol homeostasis and delineate the role of Smads-2 and ‐3 during this process. Western blot analysis showed that TGF-β induces a rapid phosphorylation-dependent activation of Smad-2 and ‐3 in THP-1 and primary human monocyte-derived macrophages. Small interfering RNA-mediated knockdown of Smad-2/3 expression showed that the TGF-β-mediated regulation of key genes implicated in the uptake of modified low density lipoproteins and the efflux of cholesterol from foam cells was Smad-dependent. Additionally, through the use of virally delivered Smad-2 and/or Smad-3 short hairpin RNA, we demonstrate that TGF-β inhibits the uptake of modified LDL by macrophages through a Smad-dependent mechanism and that the TGF-β-mediated regulation of CD36, lipoprotein lipase and scavenger receptor-A gene expression was dependent on Smad-2. These studies reveal a crucial role for Smad signaling, particularly Smad-2, in the inhibition of foam cell formation by TGF-β through the regulation of expression of key genes involved in the control of macrophage cholesterol homeostasis., Highlights ► Anti-atherogenic cytokine TGF-β inhibits macrophage foam cell formation. ► The role of Smads in the control of macrophage cholesterol homeostasis was studied. ► Smads were found to play a key role in the TGF-β-mediated uptake of modified LDL. ► A dominant role of Smad2 was identified in the regulation of gene expression. ► The TGF-β-Smad axis may represent a powerful anti-foam cell therapeutic target.