Trimethylamine N-oxide (TMAO), which is oxidized from trimethylamine (TMA) by hepatic flavin-containing monooxygenases (FMOs), promotes the development of atherosclerosis and is a new target for the prevention and treatment of cardiovascular disease from the perspective of intestinal flora. TMA is transformed by intestinal flora from TMA-containing nutrients, such as choline. Some small molecular agents lower serum TMAO and/or cecal TMA levels. However, probiotics that can effectively reduce serum TMAO levels are currently lacking. In this work, five potentially probiotic strains were administered to mice supplemented with 1.3% choline. Only Lactobacillus plantarum ZDY04 significantly reduced serum TMAO and cecal TMA levels by modulating the relative abundance of the families Lachnospiraceae, Erysipelotrichaceae and Bacteroidaceae and the genus Mucispirillum in mice and not by influencing the expression levels of hepatic FMO3 and metabolizing choline, TMA, and TMAO. In addition, L. plantarum ZDY04 can significantly inhibit the development of TMAO-induced atherosclerosis in ApoE^−/− 1.3% choline-fed mice as compared with the untreated PBS group. In conclusion, the use of L. plantarum ZDY04 may be an alternative approach to reduce serum TMAO levels and TMAO-induced atherosclerosis in mice.

Macrophages polarized to different phenotypes critically contribute to colitis development by coordinating inflammatory and anti-inflammatory processes. Herein, targeting the balance between the pro-inflammatory M1 and the anti-inflammatory M2 macrophage phenotypes can be a novel therapeutic approach for colitis. In the present study, we firstly demonstrated that tiliroside possessed the ability to alleviate the clinical symptoms of colitis as evidenced by decreased disease activity index (DAI) scores, longer colon length, reduced myeloperoxidase (MPO) activity, and improvement of colonic pathological damage in vivo. Furthermore, we showed that tiliroside modulated the balance between M1 and M2 macrophages toward a more anti-inflammatory status in colonic lamina propria but has little effect on the T cell population and epithelial barrier function in colitis mice. The macrophage depletion study further showed the protective effect of tiliroside was macrophage dependent in vivo. Mechanistically, our study demonstrated that tiliroside regulated cellular metabolism by inhibiting aerobic glycolysis in LPS and IFNγ stimulated macrophages. At the molecular level, tiliroside facilitated the proteasomal degradation of HIF-1α and downregulated mRNA expressions of HIF-1α dependent glycolytic enzymes in macrophages. Collectively, our data highlight the aberrant M1/M2 macrophage polarization in the initiation and development of ulcerative colitis and put forth the stage for considering tiliroside as a metabolic regulator in reprogramming macrophage polarization, which may serve as a promising therapeutic approach for treatment of inflammation-associated and metabolic disorders.

Cardiovascular diseases are a class of heart or blood vessels diseases, which are now considered to be the leading cause of death globally. A number of recent studies have reported key roles for inflammation in the progression of diseased vessels and systematic heart failure. In particular, endoplasmic reticulum (ER) stress, which is mechanistically implicated in inflammation and autophagy, has now been associated with pathophysiological states in the cardiovascular system. Autophagy has also been identified as an important process in the progression of multiple cardiovascular diseases such as in atherosclerosis plaque progression and ischemia and/or reperfusion. In light of the above, it has been proposed that a link between inflammation, autophagy, and ER stress may exist that contribute to diseases of the heart and its supporting vessels. This review highlights current knowledge on the cross talk between these three biological processes, and the potential of targeting this pathway as a therapeutic approach for cardiovascular disorders and its related diseases.

Atherosclerosis, a chronic inflammatory disease of the arterial wall, is among the leading causes of morbidity and mortality worldwide. The persistence of low-grade vascular inflammation has been considered to fuel the development of atherosclerosis. However, fundamental mechanistic understanding of the establishment of non-resolving low-grade inflammation is lacking, and a large number of atherosclerosis-related cardiovascular complications cannot be prevented by current therapeutic regimens. Trained immunity is an emerging new concept describing a prolonged hyperactivation of the innate immune system after exposure to certain stimuli, leading to an augmented immune response to a secondary stimulus. While it exerts beneficial effects for host defense against invading pathogens, uncontrolled persistent innate immune activation causes chronic inflammatory diseases. In light of the above, the long-term over-activation of the innate immune system conferred by trained immunity has been recently hypothesized to serve as a link between non-resolving vascular inflammation and atherosclerosis. Here, we provide an overview of current knowledge on trained immunity triggered by various exogenous and endogenous inducers, with particular emphasis on its pro-atherogenic effects and the underlying intracellular mechanisms that act at both the cellular level and systems level. We also discuss how trained immunity could be mechanistically linked to atherosclerosis from both preclinical and clinical perspectives. This review details the mechanisms underlying the induction of trained immunity by different stimuli, and highlights that the intracellular training programs can be different, though partly overlapping, depending on the stimulus and the biological system. Thus, clinical investigation of risk factor specific innate immune memory is necessary for future use of trained immunity-based therapy in atherosclerosis.

Thrombospondin 2 (TSP2) can inhibit angiogenesis in vitro by limiting proliferation and inducing apoptosis of endothelial cells (ECs). TSP2 can also modulate the extracellular levels of gelatinases (matrix metalloproteases, MMPs) and potentially influence the remodeling of the extracellular matrix (ECM). Here, we tested the hypothesis that by regulating MMPs, TSP2 could alter EC-ECM interactions. By using a three-dimensional angiogenesis assay, we show that TSP2, but not TSP1, limited angiogenesis by decreasing gelatinolytic activity in situ. Furthermore, TSP2-null fibroblast-derived ECM, which contains irregular collagen fibrils, was more permissive for EC migration. Investigation of the role of TSP2 in physiological angiogenesis in vivo, using excision of the left femoral artery in both TSP2-null and wild-type mice, revealed that TSP2-null mice displayed accelerated recovery of blood flow. This increase was attributable, in part, to an enhanced arterial network in TSP2-null muscles of the upper limb. Angiogenesis in the lower limb was also increased and was associated with increased MMP-9 deposition and gelatinolytic activity. The observed changes correlated with the temporal expression of TSP2 in the ischemic muscle of wild-type mice. Taken together, our observations implicate the matrix-modulating activity of TSP2 as a mechanism by which physiological angiogenesis is inhibited.