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Highlighted articles April

Volume 259 Issue April 2017

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Apart from lipid accumulation, inflammation is a hallmark of atherosclerotic vascular disease. This issue of Atherosclerosis includes several papers from basic, translational and population research reporting on old and new players in inflammation. Of note, some of them including HDL are bridges between lipid metabolism and inflammation.

Issue highlights

Articles

  • Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis
  • High density lipoproteins are modulators of protease activity: Implications in inflammation, complement activation, and atherothrombosis
  • HDL inhibits saturated fatty acid mediated augmentation of innate immune responses in endothelial cells by a novel pathway
  • PKC-epsilon and TLR4 synergistically regulate resistin-mediated inflammation in human macrophages
  • Anti-MYC-associated zinc finger protein antibodies are associated with inflammatory atherosclerotic lesions on 18F-fluorodeoxyglucose positron emission tomography

    Highlighted articles

    Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis

    Inconsistent findings have been reported on the association between high-sensitivity C-reactive protein (hs-CRP) and mortality risk. With this meta-analysis, Li et al. investigated the association of elevated baseline hs-CRP levels with all-cause, cardiovascular, and cancer mortality risk in the general population.

    PubMed and Embase were systematically searched for studies published from inception to October 2016. Prospective observational studies were eligible if they reported the effects of elevated baseline hs-CRP levels on cancer-related, cardiovascular or all-cause mortality in the general population. The pooled adjusted risk ratio (RR) with 95% confidence interval (CI) comparing the highest to the lowest category of hs-CRP levels was used as association measures.

    A total of 83,995 participants from 14 studies were identified. When comparing the highest to the lowest category of hs-CRP levels, the pooled RR was 1.25 for cancer-related mortality, 2.03 for cardiovascular mortality, and 1.75 for all-cause mortality. Subgroup analysis showed that elevated hs-CRP levels could predict cancer-related mortality in men but not in women.

    These results suggest that elevated hs-CRP levels can independently predict the risk of all-cause, cardiovascular mortality in the general population. However, the gender differences in the predictive role of hs-CRP on cancer mortality should to be further investigated.

    High density lipoproteins are modulators of protease activity: Implications in inflammation, complement activation, and atherothrombosis

    High density lipoproteins (HDL) represent a compositionally diverse population of particles present in the circulation, containing a wide variety of lipids and proteins. Gene ontology functional analysis of the 96 commonly identified HDL binding proteins reveals that almost half of these proteins are either proteases or have known roles in protease regulation. In this review, Gordon and Remaley discuss the role of some of these proteins in the regulation of proteases involved in inflammation, coagulation, and complement activation, particularly in the context of atherosclerosis. The authors focus on the potential functional roles of HDL in protease regulatory pathways based on current literature and known functions of HDL binding proteins, with the aim of promoting the consideration of HDL as a global modulator of the proteolytic equilibrium.

    HDL inhibits saturated fatty acid mediated augmentation of innate immune responses in endothelial cells by a novel pathway

    Peripheral insulin resistance is associated with several metabolic abnormalities, including elevated serum fatty acids that contribute to vascular injury and atherogenesis. Zhang et al. studied whether in endothelial cells saturated fatty acids can modify innate immune responses to subclinical concentrations of lipopolysaccharide (LPS), and examined whether the underlying pathway is modified by high density lipoproteins (HDL) and other factors commonly altered in insulin resistance.

    Physiologic concentrations of palmitic acid were added to human aortic endothelial cells with and without a variety of inhibitors or HDL, and cell inflammation and function were assessed.

    Palmitic acid significantly amplified human aortic endothelial cell inflammatory responses to LPS. Similar results were obtained from lipolytic products of triglyceride rich lipoproteins. The metabolism of palmitic acid to ceramide and subsequent activation of PKC-ζ, MAPK and ATF3 appeared critical in amplifying LPS-induced inflammation. The amplified response to palmitic acid/LPS was decreased by HDL in a dose dependent manner, and this inhibition was dependent on activation of PI3K/AKT and reduction in ATF3.

    These results suggest that the innate immune responses of endothelial cells are modified by metabolic abnormalities commonly present in insulin resistance and provide evidence for a novel mechanism by which HDL may reduce vascular inflammation.

    PKC-epsilon and TLR4 synergistically regulate resistin-mediated inflammation in human macrophages

    Resistin has been associated with atherosclerotic inflammation and cardiovascular complications. At a high pathological concentration, PKC-epsilon (PKCε) is involved in resistin-induced smooth muscle cell (VSMC) dysfunction. Zuniga et al. aimed at assessing the role and potential pathways of physiological concentrations of resistin in atherosclerosis-related inflammation.
    Resistin concentration was measured in plasma from patients with atherosclerosis. Patients were divided into tertiles based on resistin levels and cytokines were compared between tertiles. Macrophages were then treated with resistin in the presence or absence of PKCε inhibitor and/or TLR4 blocking-antibody, and their inflammatory state was evaluated with ELISA, RT-PCR, immunocytochemistry, and Western blot.
    Significant associations between plasma resistin levels and TNF-α, IL-6, IL-12, MIP-1α, MIP-1β, and CD40L were observed. The in vitro analysis revealed that resistin activated PKCε via TLR4, followed by NF-kB activation and induction of a pro-inflammatory phenotype, leading to the upregulation of CD40, downregulation of CD206 and stimulation of gene expression and secretion of the inflammatory cytokines for which an association was found in the plasma analysis. Resistin also induced persistent TRAM and CD40L upregulation up to 36 h after treatment. PKCε and TLR4 inhibitors suppressed gene expression to levels similar to control, especially when used in combination.
    These results show that at a physiological concentration, resistin exacerbates the inflammatory response of macrophages. PKCε is a key upstream mediator in resistin-induced inflammation that may interact synergistically with TLR4 to promote NF-kB activation, while TRAM is an important signal. PKCε and TRAM may represent novel molecular targets for resistin-associated chronic atherosclerotic inflammation.

    Anti-MYC-associated zinc finger protein antibodies are associated with inflammatory atherosclerotic lesions on 18F-fluorodeoxyglucose positron emission tomography

    A growing body of evidence supports an autoimmune component to atherosclerosis. Ernst et al. aimed at evaluating a novel autoantibody against MYC-associated zinc finger protein (MAZ-Ab) as a potential marker of atherosclerosis. They compared MAZ-Ab to activity attributable to atherosclerosis on whole-body positron-emission tomography/computed tomography (PET/CT).

    An antibody screening using protein arrays was performed in patients with angiographically-proven ischaemic heart disease. Following MAZ-Ab detection, an ELISA for large-scale testing was developed. An a priori group of unselected patients undergoing unrelated 18F-fluorodeoxyglucose (FDG) PET/CT was prospectively enrolled. Each patient completed a structured questionnaire under supervision and serum was taken for analysis. PET/CT scans were analyzed for inflammatory arterial lesions. Whole-body arterial inflammatory burden was then correlated with ELISA optical density for MAZ-Ab.

    Protein array testing identified anti-MAZ IgG antibodies in four of six patients with ischemic heart disease but non among ten controls. Significant positive correlations between MAZ-Ab and both increasing number of PET positive inflammatory atherosclerostic lesions and whole-body arterial inflammatory burden were shown. No traditional atherosclerotic risk factor correlated with MAZ-Ab.

    A quantitative association between MAZ-Ab optical density on ELISA and the cumulative inflammatory burden of atherosclerosis on 18F-FDG PET/CT was shown. These results provide further evidence for an autoimmune component in atherosclerosis and suggest MAZ-Abs as a potential biomarker for atherosclerotic disease.

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