Circulating Levels of Interleukin 1-Receptor Antagonist and Risk of Cardiovascular Disease

Herder, Christian; Gala, Tonia de las Heras; Carstensen‐Kirberg, Maren; Huth, Cornelia; Zierer, Astrid; Wahl, Simone; Sudduth-Klinger, Julie; Kuulasmaa, Kari; Peretz, David; Ligthart, Symen; Bongaerts, Brenda; Dehghan, Abbas; Ikram, M. Arfan; Jula, Antti; Kee, Frank; Pietilä, Arto; Saarela, Olli; Zeller, Tanja; Blankenberg, Stefan; Meisinger, Christa; Peters, Annette; Roden, Michael; Salomaa, Veikko; Köenig, Wolfgang; Thorand, Barbara

doi:10.1161/atvbaha.117.309307

Cited by 85 publications

(57 citation statements)

References 35 publications

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“…It might be surprising that high SFRP5 was associated with lower levels of the anti-inflammatory IL-1Ra which argues against an anti-inflammatory action of SFRP5 at a first glance. However, prospective studies clearly demonstrated that higher IL-1Ra levels were associated with a higher risk of type 2 diabetes and cardiovascular events [33–35]. This association may at least partially reflect a response to proatherogenic factors such as subclinical inflammation (including IL-1β-mediated processes, which upregulate IL-1Ra) and oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Inverse associations between serum levels of secreted frizzled-related protein-5 (SFRP5) and multiple cardiometabolic risk factors: KORA F4 study

Carstensen‐Kirberg

Kannenberg

Huth

et al. 2017

Cardiovasc Diabetol

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AimsSecreted frizzled-related protein (Sfrp)5 has beneficial effects on insulin sensitivity, inflammation and cardiovascular risk in different mouse models, but its relevance for cardiometabolic diseases in humans is controversial. We aimed to characterise associations of circulating SFRP5 with cardiometabolic risk factors and prediabetes/type 2 diabetes in a large population-based cohort.MethodsCross-sectional associations between serum SFRP5 and cardiometabolic risk factors as well as prediabetes/type 2 diabetes were investigated in 1096 participants aged 62–81 years from the German KORA F4 study, of whom 666 had prediabetes or type 2 diabetes. Multivariable linear regression models were adjusted for potential confounders including age, sex, body mass index (BMI), lifestyle factors, lipids, hypertension, kidney function and myocardial infarction.ResultsHigher serum SFRP5 levels were associated with lower HbA1c, BMI, systolic blood pressure, estimated glomerular filtration rate and high-sensitivity C-reactive protein levels and with higher levels of high-density lipoprotein cholesterol and adiponectin in the fully adjusted model (all P < 0.009). In contrast, favourable associations between SFRP5 and glycaemia, insulin, insulin resistance and other cardiometabolic risk factors were attenuated after adjustment for BMI. Serum SFRP5 levels were lower in participants with prediabetes or type 2 diabetes [(median (25th; 75th percentile) 48.8 (35.5; 65.7) ng/ml] compared to participants with normal glucose tolerance [55.9 (42.6; 69.6) ng/ml] (P < 0.001). In the fully adjusted model, higher SFRP5 was associated with lower odds of prediabetes/type 2 diabetes [OR (95% CI) (0.72 (0.58; 0.89)) per doubling of SFRP5, P < 0.01].ConclusionsHigher serum SFRP5 was inversely associated with multiple risk factors for type 2 diabetes and cardiovascular diseases. However, BMI represents a strong confounder of some of these associations. Higher circulating SFRP5 was also associated with lower odds of prediabetes/type 2 diabetes, and this association was independent of BMI. Thus, SFRP5 emerges as novel biomarker that merits further research in the context of prevention of cardiometabolic diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0591-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Inverse associations between serum levels of secreted frizzled-related protein-5 (SFRP5) and multiple cardiometabolic risk factors: KORA F4 study

Carstensen‐Kirberg

Kannenberg

Huth

et al. 2017

Cardiovasc Diabetol

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“…Furthermore, a recent meta-analysis has shown a positive association between higher serum levels of IL-1 receptor antagonist and increased incidence of cardiovascular disease in the general population. 56 Based on the inflammatory hypothesis of atherosclerotic cardiovascular diseases, a large-scale randomized clinical trial is currently ongoing to elucidate whether targeting IL-1β can reduce the risk of recurrent cardiovascular events (the CANTOS trial [canakinumab anti-inflammatory thrombosis outcomes study]). 57 A novel link between inflammation and coronary endothelial dysfunction has been reported from the Lerman laboratory; human coronary endothelial dysfunction was more severe in coronary artery segments with macrophage infiltration and vasa vasorum proliferation in an additive manner than in those without them, indicating an important role of inflammation and vasa vasorum proliferation in the pathogenesis of coronary artery disease.…”

Section: Hallmark Of Disease Inflammationmentioning

confidence: 99%

Endothelial Functions

Godo

Shimokawa

2017

ATVB

376

258

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e108T he endothelium plays important roles in modulating vascular tone by synthesizing and releasing an array of endothelium-derived relaxing factors, including vasodilator prostaglandins, NO, and endothelium-dependent hyperpolarization (EDH) factors, as well as endothelium-derived contracting factors.1,2 Such redundant mechanisms, like endogenous hyperglycemic hormones, are advantageous for ensuring proper maintenance of vascular tone under pathological conditions, where one of the vasoactive factor-mediated responses is compromised favoring a vasoconstrictor, prothrombotic, and proinflammatory state. Endothelial dysfunction is mainly caused by reduced production or action of endothelium-derived relaxing factors and could be an initial step toward cardiovascular disease.1 Indeed, evaluation of endothelial functions in humans has attracted much attention in the clinical settings because it serves as an excellent surrogate marker of cardiovascular events. For instance, endothelial dysfunction, as evaluated by impaired flow-mediated dilation of the brachial artery or digital reactive hyperemia index in peripheral arterial tonometry, is associated with future cardiovascular events in patients with coronary artery disease, 3-5 and 1-SD decrease in flow-mediated dilation or reactive hyperemia index is associated with doubling of cardiovascular event risk. 6 These observations suggest that endothelial function in peripheral vascular beds could predict future cardiovascular events.In this review, we will sum up the current advances and trends in the research on endothelial functions from bench to bedside with particular focus on recent publications in Arteriosclerosis, Thrombosis, and Vascular Biology. Earlier highlights of the journal on endothelial biology are extensively summarized in some review articles. 7-9 Emerging Modulators of Endothelial Functions Shear StressAs Lüscher and Corti 10 described in an editorial, flow is the signal of life. This physical force is sensed by the endothelium lining internal surface of the whole cardiovascular system to be translated into numerous downstream signaling pathways in a moment to moment manner in response to diverse physiological demands in the body. Indeed, shear stress is one of the important physiological cues that make endothelial cells synthesize and release endothelium-derived relaxing factors to cause relaxation of underlying vascular smooth muscle and vasodilatation. In this context, novel mechanisms of endothelial mechanotransduction in health and disease have been unveiled and summarized in a review series published recently in Arteriosclerosis, Thrombosis, and Vascular Biology. 11,12 Briefly, Zhou et al 12 emphasized the distinct roles of atheroprotective laminar or pulsatile shear stress versus atheroprone oscillatory shear stress or disturbed flow and discussed in detail the underlying molecular mechanisms that are dependent on these patterns of flow. Abe and Berk 11 further reviewed the current knowledge on the dual roles of shear stress with emphasis plac...

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“…In DPN, increased IL-1RA levels reflect compensatory upregulation in response to IL-1b dysregulation with low-grade inflammatory diseases. Recombinant IL-1RA and IL-1b inhibitor used in clinical trials were required for clarification of the inflammatory process role in the progression of DPN 7 .…”

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confidence: 99%