scholarly journals Modulating Autoimmunity against LDL: Development of a Vaccine against Atherosclerosis

2021 ◽  
Vol 41 (06) ◽  
pp. 447-457
Author(s):  
Timoteo Marchini ◽  
Tijani Abogunloko ◽  
Dennis Wolf
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Experimental Atherosclerosis ◽  
Chronic Inflammatory Disease ◽  
Autoimmune Response ◽  
Atherosclerotic Plaques ◽  
Low Grade ◽  
Main Protein ◽  
Specific Antigens ◽  
Traditional Risk Factors

AbstractAtherosclerosis is a chronic inflammatory disease of the arterial wall that leads to the build-up of occluding atherosclerotic plaques. Its clinical sequelae, myocardial infarction and stroke, represent the most frequent causes of death worldwide. Atherosclerosis is a multifactorial pathology that involves traditional risk factors and chronic low-grade inflammation in the atherosclerotic plaque and systemically. This process is accompanied by a strong autoimmune response that involves autoreactive T cells in lymph nodes and atherosclerotic plaques, as well as autoantibodies that recognize low-density lipoprotein (LDL) and its main protein component apolipoprotein B (ApoB). In the past 60 years, numerous preclinical observations have suggested that immunomodulatory vaccination with LDL, ApoB, or its peptides has the potential to specifically dampen autoimmunity, enhance tolerance to atherosclerosis-specific antigens, and protect from experimental atherosclerosis in mouse models. Here, we summarize and discuss mechanisms, challenges, and therapeutic opportunities of immunomodulatory vaccination and other strategies to enhance protective immunity in atherosclerosis.

scholarly journals IL-33 reduces the development of atherosclerosis

2008 ◽  
Vol 205 (2) ◽  
pp. 339-346 ◽  
Author(s):  
Ashley M. Miller ◽  
Damo Xu ◽  
Darren L. Asquith ◽  
Laura Denby ◽  
Yubin Li ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Protective Role ◽  
Chronic Inflammatory Disease ◽  
Total Serum ◽  
Atherosclerotic Plaques ◽  
Aortic Sinus ◽  
Serum Iga ◽  
Lymph Node Cells ◽  
Atherosclerosis Development

Atherosclerosis is a chronic inflammatory disease of the vasculature commonly leading to myocardial infarction and stroke. We show that IL-33, which is a novel IL-1–like cytokine that signals via ST2, can reduce atherosclerosis development in ApoE−/− mice on a high-fat diet. IL-33 and ST2 are present in the normal and atherosclerotic vasculature of mice and humans. Although control PBS-treated mice developed severe and inflamed atherosclerotic plaques in the aortic sinus, lesion development was profoundly reduced in IL-33–treated animals. IL-33 also markedly increased levels of IL-4, -5, and -13, but decreased levels of IFNγ in serum and lymph node cells. IL-33 treatment also elevated levels of total serum IgA, IgE, and IgG1, but decreased IgG2a, which is consistent with a Th1-to-Th2 switch. IL-33–treated mice also produced significantly elevated antioxidized low-density lipoprotein (ox-LDL) antibodies. Conversely, mice treated with soluble ST2, a decoy receptor that neutralizes IL-33, developed significantly larger atherosclerotic plaques in the aortic sinus of the ApoE−/− mice compared with control IgG-treated mice. Furthermore, coadministration of an anti–IL-5 mAb with IL-33 prevented the reduction in plaque size and reduced the amount of ox-LDL antibodies induced by IL-33. In conclusion, IL-33 may play a protective role in the development of atherosclerosis via the induction of IL-5 and ox-LDL antibodies.

scholarly journals Reduction of Vascular Inflammation, LDL-C, or Both for the Protection from Cardiovascular Events?

2018 ◽  
Vol 12 (1) ◽  
pp. 29-40 ◽  
Author(s):  
Andromachi Reklou ◽  
Michael Doumas ◽  
Konstantinos Imprialos ◽  
Konstantinos Stavropoulos ◽  
Dimitris Patoulias ◽  
...  
Keyword(s):  
Vascular Inflammation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Myocardial Damage ◽  
Lipid Lowering ◽  
Human Antibody ◽  
Low Grade ◽  
Cvd Risk ◽  
Expensive Drug ◽  
Arterial Inflammation

Background: Low density lipoprotein cholesterol (LDL-C) and low grade arterial inflammation are key pathogenic factors for atherosclerosis and its manifestation, cardiovascular disease (CVD). Objective: In this narrative review we assessed if decreasing LDL-C levels or inflammation or both is more effective in reducing CVD events. Results: In the Scandinavian Simvastatin Survival Study (4S), all statin trials of the 90s’ and the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) the benefit came from the LDL-C reduction. In the GREak and Atorvastatin Coronary heart disease Evaluation (GREACE), the Treating to New Targets (TNT), and the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trials both mechanisms in combination produced significant benefits. In the Atorvastatin for Reduction of MYocardial Damage during Angioplasty (ARMYDA) trials and the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) with a human antibody targeting IL-1β with no lipid lowering effect, the reduction in arterial inflammation played the only beneficial role because there was no change in lipids levels. Conclusion: Both LDL-C and inflammation reduction are beneficial to the reduction of CVD risk. However, canakinumab is a very expensive drug that only induced a 15% reduction in CVD events, thus drastically reducing the possibility for it to be used in clinical practice. Besides, canakinumab is associated with increased infections, some fatal. A potent statin with anti-inflammatory effects is probably the best choice for the majority of those needing hypolipidaemic drug therapy.

scholarly journals KORELASI KADAR HIGH SENSITIVITY C-REACTIVE PROTEIN DENGAN KADAR LOW DENSITY LIPOPROTEIN PADA PENYANDANG OBES

2020 ◽  
Vol 5 (3) ◽  
pp. 676
Author(s):  
Rama Dhanivita Djamin
Keyword(s):  
Interleukin 1 ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
High Sensitivity ◽  
Low Grade ◽  
Low Density ◽  
C Reactive Protein ◽  
Necrosis Factor Alpha ◽  
Reactive Protein ◽  
Hs Crp

<p><em>Obesitas terjadi karena akumulasi lemak berlebih di dalam tubuh. Akumulasi lemak menimbulkan low grade inflammation pada jaringan adiposa, menyebabkan peningkatan sitokin inflamasi seperti tumor necrosis factor-alpha, interleukin-1 beta, dan interleukin-6 (IL-6). Peningkatan sekresi IL-6 merangsang hepar meningkatkan produksi protein fase akut. High sensitivity C-reactive protein (hs-CRP) sebagai penanda inflamasi merupakan protein fase akut. Low density lipoprotein (LDL-kolesterol) adalah lipoprotein yang paling banyak mengandung kolesterol. Peningkatan kadar hs-CRP dan kadar LDL-kolesterol pada obesitas diidentifikasi sebagai faktor risiko aterosklerosis. Penelitian ini bertujuan menganalisis hubungan hs-CRP dengan LDL-kolesterol pada penyandang obes, merupakan penelitian analitik rancangan potong lintang dilakukan  September 2018 sampai Agustus 2019. Kadar hs-CRP diperiksa dengan metode enzyme linked immunoassay (ELISA), sedangkan kadar LDL-kolesterol dengan metode kalkulasi (rumus Friedewald). Uji korelasi Spearman digunakan untuk menganalisi data, jika didapatkan nilai p&lt;0,05 korelasi dinyatakan bermakna. Subjek penelitian berjumlah 26 penyandang obes terdiri dari 6 laki-laki (23,1%) dan 20 perempuan (76,9%). Rerata umur subjek penelitian adalah 36,46(7,68) tahun. Rerata kadar hs-CRP dan kadar LDL-kolesterol adalah 5,08(1,28) mg/L dan  154,69(45,8) mg/dL. Analisis korelasi menunjukkan korelasi positif lemah dan tidak bermakna secara statistik antara kadar hs-CRP dengan kadar LDL-kolesterol (r= 0,333, p=0,096). Simpulan: Terdapat korelasi positif lemah antara kadar hs-CRP dengan kadar LDL-kolesterol pada penyandang obes.</em></p><p><strong><em>Kata kunci</em></strong><em>: </em><em>Obesitas, High Sensitivity C-Reactive, Low Density Lipoprotein</em><em></em></p>

Plasma protein synthesis in patients with low-grade nephrotic proteinuria

2001 ◽  
Vol 280 (4) ◽  
pp. E591-E597 ◽  
Author(s):  
Michela Zanetti ◽  
Rocco Barazzoni ◽  
Giacomo Garibotto ◽  
Gloria Davanzo ◽  
Carlo Gabelli ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Grade ◽  
Albumin Concentration ◽  
Turnover Rates ◽  
Plasma Albumin ◽  
Nephrotic Proteinuria ◽  
Plasma Albumin Concentration ◽  
Normal Albumin ◽  
Secretion Rates

Overt nephrotic syndrome is characterized by albumin and fibrinogen hyperproduction and reduced very low density lipoprotein apolipoprotein B-100 (VLDL apoB-100) clearance. Whether similar changes also occur in low-grade proteinuria is not known. Thus we measured albumin, fibrinogen, and VLDL apoB-100 kinetics in six patients with modest proteinuria and normal creatinine clearance (P) and in ten control subjects (C) by leucine tracer infusion and precursor-product relationships. In P, plasma albumin concentration was decreased ( P < 0.003), whereas concentrations of fibrinogen and VLDL apoB-100 were increased ( P < 0.001). In P, albumin fractional secretion rate (FSR) was increased ( P < 0.01), fibrinogen FSR was normal, and VLDL apoB-100 FSR was decreased ( P < 0.03). As a result, in P, absolute secretion rates (ASR) of albumin and fibrinogen were increased ( P < 0.03), whereas VLDL apoB-100 ASR was normal. Albumin FSR was inversely correlated to oncotic pressure in P but not in C. These findings suggest that low-grade nephrotic proteinuria is characterized by simultaneous multiple alterations in turnover rates of albumin, fibrinogen, and VLDL apoB-100. Their pathogenesis, however, appears to be multifactorial.

The molecular basis of homocysteine thiolactone-mediated vascular disease

2007 ◽  
Vol 45 (12) ◽  
Author(s):  
Hieronim Jakubowski
Keyword(s):  
Vascular Disease ◽  
Vascular System ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Autoimmune Response ◽  
Protein Targets ◽  
Homocysteine Thiolactone ◽  
Lysine Residues ◽  
Isopeptide Bonds ◽  
Chronic Activation

AbstractAccumulating evidence suggests that a metabolite of homocysteine (Hcy), the thioester Hcy-thiolactone, plays an important role in atherogenesis and thrombosis. Hcy-thiolactone levels are elevated in hyperhomocysteinemic humans and mice. The thioester chemistry of Hcy-thiolactone underlies its ability to form isopeptide bonds with protein lysine residues, which impairs or alters the protein's function. Protein targets for the modification by Hcy-thiolactone in human blood include fibrinogen, low-density lipoprotein, and high-density lipoprotein. Protein N-homocysteinylation leads to pathophysiological responses, including increased susceptibility to thrombogenesis caused by N-Hcy-fibrinogen, and an autoimmune response elicited by N-Hcy-proteins. Chronic activation of these responses in hyperhomocysteinemia over many years could lead to vascular disease. This article reviews recent evidence supporting the hypothesis that Hcy-thiolactone contributes to pathophysiological effects of Hcy on the vascular system.Clin Chem Lab Med 2007;45:1704–16.

Development of Nanoparticle Probes for In Vivo Imaging of Atherosclerotic Plaques

2012 ◽  
Author(s):  
Zihao Zhang ◽  
Sheng Tong ◽  
Gang Bao
Keyword(s):  
Surface Defects ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Necrotic Core ◽  
Intraplaque Hemorrhage ◽  
Atherosclerotic Plaques ◽  
Nanoparticle Probes ◽  
Arterial Lumen ◽  
Inflammatory Macrophage

Atherosclerosis, the formation of fatty plaques in the arterial lumen, is mediated by inflammatory macrophage infiltration in the lesion and ingestion of low-density lipoprotein (LDL), forming foam cells. Its progression will likely form a large necrotic core and fibrotic cap surface defects. The resulting intraplaque hemorrhage causes red blood cell infiltration and hemoglobin abundance, which oxidizes LDL to form cholesterol crystal aggregates (1). Hemorrhagic plaques could rupture and form artery-blocking emboli. Thus, it is critical to develop a tool to detect and locate unstable hemorrhagic plaques in live specimens.

scholarly journals Carvedilol Ameliorates Experimental Atherosclerosis by Regulating Cholesterol Efflux and Exosome Functions

2019 ◽  
Vol 20 (20) ◽  
pp. 5202 ◽  
Author(s):  
Chen ◽  
Tsui ◽  
Chuang ◽  
Chiang ◽  
Chen ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Nuclear Factor Κb ◽  
Experimental Atherosclerosis ◽  
Atherosclerotic Cardiovascular Disease ◽  
Beneficial Effects ◽  
Abca1 Expression ◽  
Density Lipoprotein Receptor ◽  
And Function

Carvedilol (Cav), a nonselective β-blocker with α1 adrenoceptor blocking effect, has been used as a standard therapy for coronary artery disease. This study investigated the effects of Cav on exosome expression and function, ATP-binding cassette transporter A1 (ABCA1) expression, and cholesterol efflux that are relevant to the process of atherosclerosis. Human monocytic (THP-1) cell line and human hepatic (Huh-7) cells were treated with Cav, and cholesterol efflux was measured. Exosomes from cell culture medium or mice serum were isolated using glycan-coated recognition beads. Low-density lipoprotein receptor knockout (ldlr−/−) mice were fed with high-fat diet and treated with Cav. Cav accentuated cholesterol efflux and enhanced the expressions of ABCA1 protein and mRNA in both THP-1 and Huh-7 cells. In addition, Cav increased expression and function of exosomal ABCA1 in THP-1 macrophage exosomes. The mechanisms were associated with inhibition of nuclear factor-κB (NF-κB) and protein kinase B (Akt). In hypercholesterolemic ldlr−/− mice, Cav enhanced serum exosomal ABCA1 expression and suppressed atherosclerosis by inhibiting lipid deposition and macrophage accumulation. Cav halts atherosclerosis by enhancing cholesterol efflux and increasing ABCA1 expression in macrophages and in exosomes, possibly through NF-κB and Akt signaling, which provides mechanistic insights regarding the beneficial effects of Cav on atherosclerotic cardiovascular disease.

scholarly journals Adaptive Immune Responses in Human Atherosclerosis

2020 ◽  
Vol 21 (23) ◽  
pp. 9322
Author(s):  
Silvia Lee ◽  
Benjamin Bartlett ◽  
Girish Dwivedi
Keyword(s):  
T Cells ◽  
Low Density Lipoprotein ◽  
Clinical Manifestations ◽  
Density Lipoprotein ◽  
Chronic Inflammatory Disease ◽  
Th2 Cells ◽  
Low Density ◽  
Heat Shock Protein 60 ◽  
Atherosclerosis Progression ◽  
Human Atherosclerosis

Atherosclerosis is a chronic inflammatory disease that is initiated by the deposition and accumulation of low-density lipoproteins in the artery wall. In this review, we will discuss the role of T- and B-cells in human plaques at different stages of atherosclerosis and the utility of profiling circulating immune cells to monitor atherosclerosis progression. Evidence supports a proatherogenic role for intraplaque T helper type 1 (Th1) cells, CD4+CD28null T-cells, and natural killer T-cells, whereas Th2 cells and regulatory T-cells (Treg) have an atheroprotective role. Several studies indicate that intraplaque T-cells are activated upon recognition of endogenous antigens including heat shock protein 60 and oxidized low-density lipoprotein, but antigens derived from pathogens can also trigger T-cell proliferation and cytokine production. Future studies are needed to assess whether circulating cellular biomarkers can improve identification of vulnerable lesions so that effective intervention can be implemented before clinical manifestations are apparent.

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