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  • 1
    Online Resource
    Online Resource
    Abstract 129: Investigation of Atherosclerosis in Association with Arthritic Inflammation
    Ovid Technologies (Wolters Kluwer Health) ; 2013
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 33, No. suppl_1 ( 2013-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 33, No. suppl_1 ( 2013-05)
    Abstract: It is well established that patients with Rheumatoid Arthritis (RA) have a higher risk of developing coronary artery disease (CAD). However, it is unclear how the inflammatory process affects atherosclerosis and what specific factors are involved. In this study, we investigated the effect of the pro-atherogenic factor hyperlipidaemia on arthritis incidence and severity. Simultaneously, we have investigated the mutation of the neutrophil cytosolic factor 1 (Ncf-1), a known genetic factor that promotes arthritis susceptibility, and MHCII H-2q on atherosclerosis development. Results We observed that diet-induced hyperlipidaemia prior to induction of collagen induced arthritis (CIA) protected mice against the disease while genetically hyperlipidemic without the use of diet, Ldlr-/- x human ApoB100 transgenic (Ldlr-/-hApoBtg), were equally susceptible to CIA compared to their heterozygous littermates. Next, we investigated Ncf-1 mutation on Ldlr-/-hApoBtg mice. Surprisingly, despite the increased inflammatory/arthritic phenotype induced by Ncf-1 mutation, no difference in the atherosclerotic lesion size was observed. Conclusions Our data shows that hyperlipidaemia-induced by diet have substantial effects on arthritis susceptibility, which in turn differs from hyperlipidaemia acquired on birth due to genetic alterations. By developing a model carrying pro-arthritogenic factors, MHCII H-2q and Ncf-1 mutation, as well as the pro-atherosclerotic factors, Ldlr-/- and hApoBtg, we have established a new model where both arthritis and atherosclerosis are present. These mice will be used to further characterize the impact of systemic inflammation in the form of arthritis in the atherosclerotic process and vice versa.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.33.suppl_1.A129
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2013
    detail.hit.zdb_id: 1494427-3
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  • 2
    Online Resource
    Online Resource
    Smooth muscle αv integrins regulate vascular fibrosis via CD109 downregulation of TGF-β signalling
    Oxford University Press (OUP) ; 2023
    In:  European Heart Journal Open Vol. 3, No. 2 ( 2023-03-02)
    Details
    In: European Heart Journal Open, Oxford University Press (OUP), Vol. 3, No. 2 ( 2023-03-02)
    Abstract: αv integrins are implicated in fibrosis in a number of organs through their ability to activate TGF-β. However their role in vascular fibrosis and collagen accumulation is only partially understood. Here we have used αv conditional knockout mice and cell lines to determine how αv contributes to vascular smooth muscle cell (VSMC) function in vascular fibrosis and the role of TGF-β in that process. Methods and results Angiotensin II (Ang II) treatment causes upregulation of αv and β3 expression in the vessel wall, associated with increased collagen deposition. We found that deletion of αv integrin subunit from VSMCs (αvSMKO) protected mice against angiotensin II-induced collagen production and assembly. Transcriptomic analysis of the vessel wall in αvSMKO mice and controls identified a significant reduction in expression of fibrosis and related genes in αvSMKO mice. In contrast, αvSMKO mice showed prolonged expression of CD109, which is known to affect TGF-β signalling. Using cultured mouse and human VSMCs, we showed that overexpression of CD109 phenocopied knockdown of αv integrin, attenuating collagen expression, TGF-β activation, and Smad2/3 signalling in response to angiotensin II or TGF-β stimulation. CD109 and TGF-β receptor were internalized in early endosomes. Conclusion We identify a role for VSMC αv integrin in vascular fibrosis and show that αv acts in concert with CD109 to regulate TGF-β signalling.
    Type of Medium: Online Resource
    ISSN: 2752-4191
    URL: Article
    DOI: 10.1093/ehjopen/oead010
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 3112907-9
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  • 3
    Online Resource
    Online Resource
    High-circulating gut microbiota-dependent metabolite trimethylamine N-oxide is associated with poor prognosis in pulmonary arterial hypertension
    Oxford University Press (OUP) ; 2022
    In:  European Heart Journal Open Vol. 2, No. 5 ( 2022-09-05)
    Details
    In: European Heart Journal Open, Oxford University Press (OUP), Vol. 2, No. 5 ( 2022-09-05)
    Abstract: We aimed to examine the hypothesis that circulating trimethylamine-N-oxide (TMAO) levels serve as a biomarker in pulmonary arterial hypertension (PAH), and to determine whether 3,3-dimethyl-1-butanol (DMB), a TMAO inhibitor, exerted a protective effect in monocrotaline (MCT)-induced PAH rats. Methods and results In-patients with PAH were prospectively recruited from the Fuwai Hospital. Fasting blood samples were obtained to assess the TMAO levels and other laboratory values during the initial and second hospitalization. In a MCT-induced PAH rat, a normal diet and water supplemented with or without 1% DMB were administered for 4 weeks. The TMAO levels, haemodynamic examinations, changes in organ-tissue, and molecular levels were evaluated. In total, 124 patients with PAH were enrolled in this study. High TMAO levels were correlated with increased disease severity and poor prognosis even after adjusting for confounders. The TMAO levels in the rats decreased in the MCT + DMB group, accompanied by improved haemodynamic parameters, decreased right ventricular hypertrophy, and amelioration of pulmonary vascular remodelling. The decrease in abnormal apoptosis, excessive cell proliferation, transforming growth factor-β expression, and restoration of endothelial nitric oxide synthase after DMB treatment further explained the amelioration of PAH. Conclusion Increased TMAO levels were associated with poor prognosis in patients with PAH, and DMB played a protective effect in MCT-induced PAH rat.
    Type of Medium: Online Resource
    ISSN: 2752-4191
    URL: Article
    DOI: 10.1093/ehjopen/oeac021
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 3112907-9
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  • 4
    Online Resource
    Online Resource
    Hyperlipidaemia elicits an atypical, T helper 1–like CD4+ T-cell response: a key role for very low-density lipoprotein
    Oxford University Press (OUP) ; 2023
    In:  European Heart Journal Open Vol. 3, No. 2 ( 2023-03-02)
    Details
    In: European Heart Journal Open, Oxford University Press (OUP), Vol. 3, No. 2 ( 2023-03-02)
    Abstract: Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells. Methods and results In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways. VLDL was taken up via a CD36-dependent pathway and resulted in membrane stiffening and a reduction in lipid rafts. To further detail this response in vivo, T cells of mice lacking the LDL receptor (LDLr), which develop a strong increase in VLDL cholesterol and triglyceride levels upon high cholesterol feeding were investigated. CD4+ T cells of hyperlipidemic Ldlr-/- mice exhibited an increased expression of the C-X-C-chemokine receptor 3 (CXCR3) and produced more interferon-γ (IFN-γ). Gene set enrichment analysis identified IFN-γ-mediated signaling as the most upregulated pathway in hyperlipidemic T cells. However, the classical Th1 associated transcription factor profile with strong upregulation of Tbet and Il12rb2 was not observed. Hyperlipidemia did not affect levels of the CD4+ T cell's metabolites involved in glycolysis or other canonical metabolic pathways but enhanced amino acids levels. However, CD4+ T cells of hyperlipidemic mice showed increased cholesterol accumulation and an increased arachidonic acid (AA) to docosahexaenoic acid (DHA) ratio, which was associated with inflammatory T cell activation. Conclusions Hyperlipidemia, and especially its VLDL component induces an atypical Th1 response in CD4+ T cells. Underlying mechanisms include CD36 mediated uptake of VLDL, and an altered AA/DHA ratio.
    Type of Medium: Online Resource
    ISSN: 2752-4191
    URL: Article
    DOI: 10.1093/ehjopen/oead013
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 3112907-9
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  • 5
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    Online Resource
    Combination of Sacubitril/Valsartan and Blockade of the PI3K Pathway Enhanced Kidney Protection in a Mouse Model of Cardiorenal Syndrome
    Oxford University Press (OUP) ; 2023
    In:  European Heart Journal Open
    Details
    In: European Heart Journal Open, Oxford University Press (OUP)
    Abstract: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection. Methods C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL-M, ANS-VAL-H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. Results The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signaling pathway compared with the ANS-VAL-M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL-M while preserving the superior cardioprotective effect of ARNI. Conclusions PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria.
    Type of Medium: Online Resource
    ISSN: 2752-4191
    URL: Article
    DOI: 10.1093/ehjopen/oead098
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 3112907-9
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  • 6
    Online Resource
    Online Resource
    Interplay between hypercholesterolaemia and inflammation in atherosclerosis: Translating experimental targets into clinical practice
    Oxford University Press (OUP) ; 2018
    In:  European Journal of Preventive Cardiology Vol. 25, No. 9 ( 2018-06), p. 948-955
    Details
    In: European Journal of Preventive Cardiology, Oxford University Press (OUP), Vol. 25, No. 9 ( 2018-06), p. 948-955
    Abstract: Dyslipidaemia and inflammation are closely interconnected in their contribution to atherosclerosis. In fact, low-density lipoprotein (LDL)-lowering drugs have anti-inflammatory effects. The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) has shown that interleukin (IL)-1β blockade reduces the incidence of cardiovascular events in patients with previous myocardial infarction and C-reactive protein levels 〉 2 mg/L. These data confirm the connection between lipids and inflammation, as lipids activate the Nod-like receptor protein 3 inflammasome that leads to IL-1β activation. LDL-lowering drugs are the foundation of cardiovascular prevention. Now, the CANTOS trial demonstrates that combining them with IL-1β blockade further decreases the incidence of cardiovascular events. However, both therapies are not at the same level, given the large evidence showing that LDL-lowering drugs reduce cardiovascular risk as opposed to only one randomized trial of IL-1β blockade. In addition, IL-1β blockade has only been studied in patients with C-reactive protein 〉 2 mg/L, while the benefit of LDL-lowering is not restricted to these patients. Also, lipid-lowering drugs are not harmful even at very low ranges of LDL, while anti-inflammatory therapies may confer a higher risk of developing fatal infections and sepsis. In the future, more clinical trials are needed to explore whether targeting other inflammatory molecules, both related and unrelated to the IL-1β pathway, reduces the cardiovascular risk. In this regard, the ongoing trials with methotrexate and colchicine may clarify whether the cardiovascular benefit of IL-1β blockade extends to other anti-inflammatory mechanisms. A positive result would represent a major change in the future treatment of atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 2047-4873 , 2047-4881
    URL: Article
    DOI: 10.1177/2047487318773384
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2646239-4
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  • 7
    Online Resource
    Online Resource
    Modulation of Autoimmunity and Atherosclerosis　– Common Targets and Promising Translational Approaches Against Disease –
    Japanese Circulation Society ; 2015
    In:  Circulation Journal Vol. 79, No. 5 ( 2015), p. 924-933
    Details
    In: Circulation Journal, Japanese Circulation Society, Vol. 79, No. 5 ( 2015), p. 924-933
    Type of Medium: Online Resource
    ISSN: 1346-9843 , 1347-4820
    URL: Article
    DOI: 10.1253/circj.CJ-15-0167
    Language: English
    Publisher: Japanese Circulation Society
    Publication Date: 2015
    detail.hit.zdb_id: 2084830-4
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