CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice

Steven, Sebastian; Dib, Mobin; Hausding, Michael; Kashani, F. Ravandi; Oelze, Matthias; Kröller‐Schön, Swenja; Hanf, Alina; Daub, Steffen; Roohani, Siyer; Gramlich, Yves; Lutgens, Esther; Schulz, Eberhard; Becker, Christian; Lackner, Karl J.; Kleinert, Hartmut; Knosalla, Christoph; Niesler, Beate; Wild, Philipp S.; Münzel, Thomas; Daiber, Andreas

doi:10.1093/cvr/cvx197

Cited by 40 publications

(44 citation statements)

References 66 publications

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“…In these experiments, we observed that pre-incubation of aorta segments with antioxidants improved the vascular relaxation in response to Ach in untreated obese mice but not in aorta segments from lean and obese mice supplemented with CSAT+ ® . Thus, these results clearly denote a higher oxidative status in aorta segments from untreated obese mice compared to both lean and CSAT+ ® -treated animals that compromises endothelial function, as it has been previously reported by other authors [53][54][55].…”

Section: Discussionsupporting

confidence: 87%

Supplementation with a Carob (Ceratonia siliqua L.) Fruit Extract Attenuates the Cardiometabolic Alterations Associated with Metabolic Syndrome in Mice

et al. 2020

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The incidence of metabolic syndrome (MetS) is increasing worldwide which makes necessary the finding of new strategies to treat and/or prevent it. The aim of this study was to analyze the possible beneficial effects of a carob fruit extract (CSAT+®) on the cardiometabolic alterations associated with MetS in mice. 16-week-old C57BL/6J male mice were fed for 26 weeks either with a standard diet (chow) or with a diet rich in fats and sugars (HFHS), supplemented or not with 4.8% of CSAT+®. CSAT+® supplementation reduced blood glucose, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) and circulating levels of total cholesterol, low-density lipoprotein (LDL) cholesterol (LDL-c), insulin, and interleukin-6 (IL-6). In adipose tissue and skeletal muscle, CSAT+® prevented MetS-induced insulin resistance, reduced macrophage infiltration and the expression of pro-inflammatory markers, and up-regulated the mRNA levels of antioxidant markers. Supplementation with CSAT+® prevented MetS-induced hypertension and decreased the vascular response of aortic rings to angiotensin II (AngII). Moreover, treatment with CSAT+® attenuated endothelial dysfunction and increased vascular sensitivity to insulin. In the heart, CSAT+® supplementation reduced cardiomyocyte apoptosis and prevented ischemia-reperfusion-induced decrease in cardiac contractility. The beneficial effects at the cardiovascular level were associated with a lower expression of pro-inflammatory and pro-oxidant markers in aortic and cardiac tissues.

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Section: Discussionsupporting

confidence: 87%

Supplementation with a Carob (Ceratonia siliqua L.) Fruit Extract Attenuates the Cardiometabolic Alterations Associated with Metabolic Syndrome in Mice

et al. 2020

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“…It is worth noting that a HFD had only a small influence on the CES levels in the plasma of the mice (data not shown), which was consistent with the reported research [37]. At the same time, we found that the levels of inflammatory factors TNF-α, IL-1β, and IL-6 in the liver and the intestine of the HFD mice were significantly higher than those in the control mice, in accordance with the clinical outcomes [38][39][40]. It was suggested that a HFD could inhibit the expression and activity of CES of mice, which was probably caused by the severe inflammation accompanying the HFD.…”

Section: Discussionsupporting

confidence: 91%

“…An HFD appeared to induce a slight upregulation of CES in the plasma [37]. In this case, it is noteworthy that patients with hyperlipidemia tended to be accompanied by an inflammatory response [38][39][40]. Numerous reports have described that the significantly increased secretion of various cytokines under pathological circumstances such as inflammation and infection is accompanied by the significantly decreased hydrolytic metabolism of multiple drugs.…”

Section: Introductionmentioning

confidence: 91%

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Isoflavones enhance pharmacokinetic exposure of active lovastatin acid via the upregulation of carboxylesterase in high-fat diet mice after oral administration of Xuezhikang capsules

Dong

Tan

et al. 2018

Acta Pharmacol Sin

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Xuezhikang capsule (XZK) is a traditional Chinese medicine that contains lovastatin (Lv) for hyperlipidemia treatment, although it has fewer side effects than Lv. However, the pharmacokinetic mechanisms contributing to its distinct efficacy and low side effects are unclear. Mice were fed a high-fat diet (HFD) for 6 weeks to induce hyperlipidemia. We first conducted the pharmacokinetic studies in HFD mice following oral administration of Lv (10 mg/kg, i.g.) and found that HFD remarkably decreased the active form of Lv (the lovastatin acid, LvA) exposure in the circulation system, especially in the targeting organ liver, with a declined conversion from Lv to LvA, whereas the Lv (responsible for myotoxicity) exposure in muscle markedly increased. Then we compared the pharmacokinetic profiles of Lv in HFD mice after the oral administration of XZK (1200 mg/kg, i.g.) or an equivalent dose of Lv (10 mg/kg, i.g.). A higher exposure of LvA and lower exposure of Lv were observed after XZK administration, suggesting a pharmacokinetic interaction of some ingredients in XZK. Further studies revealed that HFD promoted the inflammation and inhibited carboxylesterase (CES) activities in the intestine and the liver, thus contributing to the lower transformation of Lv into LvA. In contrast, XZK inhibited the inflammation and upregulated CES in the intestine and the liver. Finally, we evaluated the effects of monacolins and phytosterols, the fractional extracts of isoflavones, on inflammatory LS174T or HepG2 cells, which showed that isoflavones inhibited inflammation, upregulated CES, and markedly enhanced the conversion of Lv into LvA. For the first time, we provide evidence that isoflavones and Lv in XZK act in concert to enhance the efficacy and reduce the side effects of Lv.

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“…Our studies also emphasize the need to identify novel therapies inhibiting T cell activation and their recruitment in cardiovascular diseases. 35,36 In summary, we have identified that miR-214 is an essential regulator of T cell dependent mechanisms of vascular stiffening, fibrosis, and dysfunction in hypertension. It may represent a novel biomarker and a possible target for modulation of perivascular inflammation.…”

Section: Discussionmentioning

confidence: 95%

T-Cell–Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension

Nosalski

Siedliński

Denby

et al. 2020

Circulation Research

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Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. OBJECTIVES: To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. METHODS AND RESULTS: Out of 381 miRs screened in the perivascular tissues in response to Ang II (angiotensin II)-mediated hypertension, miR-214 showed the highest induction (8-fold, P=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in perivascular adipose tissue adipocytes. Global deletion of miR-214 −/− prevented Ang II-induced periaortic fibrosis, Col1a1, Col3a1, Col5a1, and Tgfb1 expression, hydroxyproline accumulation, and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214 −/− mice were protected against endothelial dysfunction, oxidative stress, and increased Nox2, all of which were induced by Ang II in WT mice. Ang IIinduced recruitment of T cells into perivascular adipose tissue was abolished in miR-214 −/− mice. Adoptive transfer of miR-214 −/− T cells into RAG1 −/− mice resulted in reduced perivascular fibrosis compared with the effect of WT T cells. Ang II induced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214 −/−. T cell activation, proliferation and chemotaxis pathways were differentially affected. MiR-214 −/− prevented Ang II-induction of profibrotic T cell cytokines (IL-17, TNF-α, IL-9, and IFN-γ) and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6, and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of patients with hypertension and is directly correlated to pulse wave velocity as a measure of vascular stiffness. CONCLUSIONS: T-cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release. VISUAL OVERVIEW: An online visual overview is available for this article.

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CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice

Abstract: CD40L controls obesity-associated vascular inflammation, oxidative stress and endothelial dysfunction in mice and potentially humans. Thus, CD40L represents a therapeutic target in lipid metabolic disorders which is a leading cause in cardiovascular disease.

Cited by 40 publications

References 66 publications

Supplementation with a Carob (Ceratonia siliqua L.) Fruit Extract Attenuates the Cardiometabolic Alterations Associated with Metabolic Syndrome in Mice

Supplementation with a Carob (Ceratonia siliqua L.) Fruit Extract Attenuates the Cardiometabolic Alterations Associated with Metabolic Syndrome in Mice

Isoflavones enhance pharmacokinetic exposure of active lovastatin acid via the upregulation of carboxylesterase in high-fat diet mice after oral administration of Xuezhikang capsules

T-Cell–Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension

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