Oridonin attenuates atherosclerosis by inhibiting foam macrophage formation and inflammation through FABP4/PPARγ signalling

Both lipid accumulation and inflammatory response in lesion macrophages fuel the progression of atherosclerosis, leading to high mortality of cardiovascular disease. A therapeutic strategy concurrently targeting these two risk factors is promising, but still scarce. Oridonin, the bioactive medicinal compound, is known to protect against inflammatory response and lipid dysfunction. However, its effect on atherosclerosis and the underlying molecular mechanism remain elusive. Here, we showed that oridonin attenuated atherosclerosis in hyperlipidemic ApoE knockout mice. Meanwhile, we confirmed the protective effect of oridonin on the oxidized low-density lipoprotein (oxLDL)-induced foam macrophage formation, resulting from increased cholesterol efflux, as well as reduced inflammatory response. Mechanistically, the network pharmacology prediction and further experiments revealed that oridonin dramatically facilitated the expression of peroxisome proliferator-activated receptor gamma (PPARγ), thereby regulating liver X receptor-alpha (LXRα)-induced ATP-binding cassette transporter A1 (ABCA1) expression and nuclear factor NF-kappa-B (NF-κB) translocation. Antagonist of PPARγ reversed the cholesterol accumulation and inflammatory response mediated by oridonin. Besides, RNA sequencing analysis revealed that fatty acid binding protein 4 (FABP4) was altered responding to lipid modulation effect of oridonin. Overexpression of FABP4 inhibited PPARγ activation and blunted the benefit effect of oridonin on foam macrophages. Taken together, oridonin might have potential to protect against atherosclerosis by modulating the formation and inflammatory response in foam macrophages through FABP4/PPARγ signalling.     

Micro-RNAs and macrophage diversity in atherosclerosis: New players,new challenges…new opportunities for therapeutic intervention?

Efforts in experimental therapeutics of atherosclerosis are mostly focused on identifying candidate targets that can be exploited in developing new strategies to reduce plaque progression, induce its regression and/or improve stability of advanced lesions. Plaque macrophages are central players in all these processes, and consequently a significant amount of research is devoted to understanding mechanisms that regulate, for instance, macrophage apoptosis, necrosis or migration. Macrophage diversity is a key feature of the macrophage population in the plaque and can impact many aspects of lesion development. Thus, searching for molecular entities that contribute to atherorelevant functions of a specific macrophage type but not others may lead to identification of targets that can be exploited in phenotype selective modulation of the lesional macrophage. This however, remains an unmet goal. In recent years several studies have revealed critical functions of micro-RNAs (miRs) in mechanisms of macrophage polarization, and a number of miRs have emerged as being specific of distinctive macrophage subsets. Not only can these miRs represent the first step towards recognition of phenotype specific targets, but they may also pave the way to reveal novel atherorelevant pathways within macrophage subsets. This article discusses some of these recent findings, speculates on their potential relevance to atherosclerosis and elaborates on the prospective use of miRs to affect the function of plaque macrophages in a phenotype selective manner.     

Tryptase promotes human monocyte-derived macrophage foam cell formation by suppressing LXRα activation

Accumulated mast cells in atherosclerotic plaques secrete a high level of tryptase that may participate in the pathogenesis of atherosclerotic disease by diverse pathways. However, the role of tryptase in the lipid metabolism of macrophages remains to be defined. In the present study, we found that the addition of tryptase into THP-1-derived macrophages increased both intracellular lipid accumulation and total cholesterol level. Tryptase promoting foam cell formation was also observed by transmission electron microscope. These effects were resisted by APC366, a selective inhibitor of mast cell tryptase. Tryptase dramatically resisted 22RHC induced activation of LXRα protein expression, which can be reversed by SAM-11 (a PAR-2-specific neutralizing antibody) and reduced LXRα, ABCG1, ABCA1 and SREBP-1c mRNA levels and ABCG1 protein level, which were all blocked by APC366. PAR-2 agonist also redeemed 22RHC stimulation to activate LXRα, ABCG1 protein expression, and mRNA levels of LXRα and its target genes in both THP-1-derived macrophages and primary human monocyte-derived macrophages. In primary macrophages that were first transfected with PAR-2 siRNA and then treated with tryptase, both the ABCG1 protein level and mRNA levels of LXRα and ABCG1 were higher than those in the control siRNA-treated cells. Taken together, our data clarified the PAR-2 expression of human macrophages and suggested that tryptase might promote lipid accumulation in macrophages and foam cell formation by suppressing LXRα activation via PAR-2/LXRα/LXRα target genes signaling pathway. This investigation sheds a new light on the role of tryptase in foam cell formation and pathogenesis of atherosclerosis.     

Cilia and the cell cycle?

A recent convergence of data indicating a relationship between cilia and proliferative diseases, such as polycystic kidney disease, has revived the long-standing enigma of the reciprocal regulatory relationship between cilia and the cell cycle. Multiple signaling pathways are localized to cilia in mammalian cells, and some proteins have been shown to act both in the cilium and in cell cycle regulation. Work from the unicellular alga Chlamydomonas is providing novel insights as to how cilia and the cell cycle are coordinately regulated.     

Borrelia burgdorferi and the macrophage: routine annihilation but occasional haven?

Borrelia burgdorferi, the agent for Lyme disease, has a typical pattern of bacterial interaction with phagocytes: attachment, stimulation o f release o f inflammatory mediators and, in most cases, ingestion and killing. Spirochetes are killed extracellulorly by antibody plus complement via the classical pathway, as well as by phagocytes through apparently nonoxidative means. Yet rare persistent spirochetes (mutants?) have been identified both in patients' tissues and in cells grown in vitro. Ruth Montgomery and Stephen Malawista here ask: are some Borrelia wolves in sheeps' clothing, evading macrophage anti-microbial action?     

Paraoxonase 1 and atherosclerosis: is the gene or the protein more important?

The oxidation of low-density lipoprotein (LDL) is centrally involved in the initiation and progression of atherosclerosis. High-density lipoprotein (HDL) paraoxonase 1 (PON1) retards the oxidation of LDL and is a major antiatherosclerotic component of HDL. The PON1 gene contains a number of functional polymorphisms in both the coding and the promoter regions, which affect either the level or the substrate specificity of PON1. Genetic case-control and prospective studies conducted to date have produced confusing results. Meta-analysis of these studies indicates no simple relationship between the PON1 polymorphisms and the presence of coronary heart disease (CHD). However, at the present moment in time, it seems that PON1 status, i.e., activity and/or concentration, is more closely related to CHD, and indeed, PON1 has shown to be an independent risk factor for CHD in a prospective study, compared to the genetic polymorphisms. PON1 levels can also be modulated by environmental\lifestyle and possibly pharmaceutical factors. Larger, better designed, preferably prospective studies are needed to determine further the association of PON1 genetic polymorphisms and status with CHD.     

Periodontal infections and atherosclerosis: mere associations?

PURPOSE OF REVIEW: Several lines of evidence from the last few decades suggest that periodontitis is an important risk factor for cardiovascular diseases. In this review we discuss the recent findings on the systemic effects of periodontitis, which may contribute to the pathogenesis of atherosclerosis, with a special emphasis on lipoproteins. RECENT FINDINGS: In addition to the epidemiological studies exploring the direct or indirect relationship between clinical periodontitis and cardiovascular diseases, studies utilizing serology, animal models, cell cultures, and biochemistry of lipoproteins have been published. Local infection in the periodontal pockets triggers a systemic inflammatory response releasing inflammatory mediators and awakens a strong immune response against periodontal pathogens. Elevated systemic antibody levels especially to Porphyromonas gingivalis are associated with an increased risk for atherosclerosis. Periodontitis is also accompanied by proatherogenic changes in both low and high density lipoproteins, which lead to enhanced cholesteryl ester uptake by and reduced cholesterol efflux from macrophages. Vesicles and lipopolysaccharide isolated from P. gingivalis activate macrophages to convert into foam cells. Moreover, animal studies have demonstrated that infection by P. gingivalis enhances progression of atherosclerosis. SUMMARY: Recent studies have clarified the mechanisms by which periodontitis may contribute to the development of atherosclerosis. Serological, animal, and cell culture studies provide evidence that infection by P. gingivalis may promote atherosclerosis. The influence of periodontitis on lipoprotein metabolism has emerged as a new, important factor. Recent studies provide experimental proof that periodontitis may predispose to atherosclerosis.     

Cellular plasticity: the good, the bad, and the ugly? Microenvironmental influences on progenitor cell therapy

Progenitor cell based therapies have emerged for the treatment of ischemic cardiovascular diseases where there is insufficient endogenous repair. However, clinical success has been limited, which challenges the original premise that transplanted progenitor cells would orchestrate repair. In this review, we discuss the basics of endothelial progenitor cell therapy and describe how microenvironmental changes (i.e., trophic and mechano-structural factors) in the damaged myocardium influence progenitor cell plasticity and hamper beneficial therapeutic outcome. Further understanding of these microenvironmental clues will enable optimization of cell therapy at all levels. We discuss current concepts and provide future perspectives for the enhancement of progenitor cell therapy, and merge these advances into a combined approach for ischemic tissue repair.     

Ran GTPase: a master regulator of nuclear structure and function during the eukaryotic cell division cycle?

Ran is an abundant GTPase that is highly conserved in eukaryotic cells and has been implicated in many aspects of nuclear structure and function, especially determining the directionality of nucleocytoplasmic transport during interphase. However, cell-free systems have recently shown that Ran plays distinct roles in mitotic spindle assembly and nuclear envelope (NE) formation in vitro. During spindle assembly, Ran controls the formation of complexes with importins, the same effectors that control nucleocytoplasmic transport. Here, we review these advances and discuss a general model for Ran in the coordination of nuclear processes throughout the cell division cycle via common biochemical mechanisms.     

Ascorbate and glutathione: guardians of the cell cycle,partners in crime?

Besides the implication of ascorbate and glutathione in the defence against oxidative stress, these two compounds are involved in plant growth and cell cycle control. Ascorbate metabolism is closely linked to the development of embryos and seedlings. Furthermore, ascorbate stimulates cell cycle activity in competent cells, while the oxidised form, dehydroascorbate, blocks normal cell cycle progression. Several possible mechanisms have been proposed to explain the effect of these compounds. The links between glutathione and the cell cycle are less clear. It has long been assumed that both compounds are closely linked by way of the Halliwell–Asada cycle. Any hypothesis concerning the pathways by which ascorbate or glutathione influence cell division, should take this connection into account. However, other mechanisms have been proposed for ascorbate-mediated cell cycle control, e.g. via the thioredoxin pathway.