amyloid-beta-peptides and Atherosclerosis

 Accumulating evidence suggests that circulating amyloidβ 1-40 (Αβ1-40), a proatherogenic aging peptide, may serve as a novel biomarker in cardiovascular disease (CVD). We aimed to explore the role of plasma Αβ1-40 and its patterns of change over time in atherosclerosis progression in postmenopausal women, a population with substantial unrecognized CVD risk beyond traditional risk factors (TRFs)..  In this prospective study, Αβ1-40 was measured in plasma by enzyme-linked immunosorbent assay and atherosclerosis was assessed using carotid high-resolution ultrasonography at baseline and after a median follow-up of 28.2 months in 152 postmenopausal women without history or symptoms of CVD..  At baseline, high Αβ1-40 was independently associated with higher carotid bulb intima-media thickness (cbIMT) and the sum of maximal wall thickness in all carotid sites (sumWT) (.  In postmenopausal women, a pattern of increasing or persistently high Αβ1-40 was associated with the rate of progression of subclinical atherosclerosis irrespective of its baseline levels. These findings provide novel insights into a link between Αβ1-40 and atherosclerosis progression in menopause and warrant further research to clarify the clinical value of monitoring its circulating levels as an atherosclerosis biomarker in women without clinically overt CVD.

Topics: Adult; Aged; Amyloid beta-Peptides; Atherosclerosis; Biomarkers; Carotid Intima-Media Thickness; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Humans; Kidney; Menopause; Middle Aged; Peptide Fragments; Prospective Studies

Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and amyloid-β(1-40) (Aβ40) emerged as markers of cardiovascular risk because of their actions in the endothelium and their role in atherosclerotic progression. The aim of this study was to analyze the association of these two factors with the decrease in carotid intima-media thickness (cIMT) after bariatric surgery in obese women.. We studied 60 severely obese women, of whom 20 were submitted to laparoscopic Roux-en-Y gastric bypass (RYGB), 20 to sleeve gastrectomy (SG), and 20 to lifestyle modification therapy. Circulating sTWEAK, Aβ40, high-sensitivity C-reactive protein, plasminogen activator inhibitor type 1, insulin resistance (HOMA-IR), and cIMT were measured at baseline and after 1 year of follow-up.. sTWEAK increased similarly after both surgical procedures, whereas the increase observed after lifestyle intervention did not reach statistical significance. Aβ40 showed no differences between groups of women, nor did it change during follow-up. The decrease in cIMT at 12 months correlated with the decrease in body mass index (BMI) (r = 0.45; p < 0.001) and fasting insulin (r = 0.30; p = 0.038), and also with the increase in sTWEAK (r = -0.43; p = 0.002). Multivariate linear regression showed that only the changes in BMI (β = 0.389; p = 0.005) and sTWEAK (β = -0.358; p = 0.009) were associated with the decrease in cIMT (R2 = 0.313; F = 9.348; p < 0.001).. One year after bariatric surgery, RYGB and SG induced a similar increase in circulating sTWEAK that occurred in parallel to the decrease observed in cIMT.

Topics: Adult; Amyloid beta-Peptides; Atherosclerosis; Bariatric Surgery; Body Mass Index; Carotid Intima-Media Thickness; Cytokine TWEAK; Female; Gastrectomy; Gastric Bypass; Humans; Male; Middle Aged; Obesity; Peptide Fragments

Homocysteine (Hcy) is considered an independent risk factor for various cardiovascular diseases including atherosclerosis which is associated with lipid metabolism, inflammation, and oxidative stress. Results from our previous study suggested that Hcy-induced atherosclerosis could be reversed by Herpud1 knockout which inhibits vascular smooth muscle cell (VSMC) phenotype switching. Here, we aim to investigate more precise mechanisms behind the improvement in Hcy-induced atherosclerosis. Amyloid-β40 (Aβ40), a vital protein in Alzheimer disease (AD), has been regarded as an important component in the atherosclerosis program in recent years due to the biological similarity between AD and atherosclerosis. Thus, we determined to assess the value of Aβ40 in a Herpud1 knockout Hcy-induced atherosclerosis mouse model by measuring Aβ40 expression in tissue and biomarkers of lipid metabolism, inflammation, and oxidative stress in serum. Additionally, since endothelial dysfunction plays a prominent role in atherosclerosis, we tested human umbilical vein endothelial cell (HUVEC) function following Herpud1 silencing in vitro and evaluated JNK/AP1 signaling activation in our models because of its close relationship with Aβ40. As a result, our animal models showed that Herpud1 knockout reduced Aβ40 expression, inflammation, and oxidative stress levels other than lipid metabolism and alleviated atherosclerosis via JNK/AP1 signaling inhibition. Similarly, our cell experiments implied that Hcy-induced Aβ40 elevation and HUVEC dysfunction involving cell proliferation and apoptosis could be restored by Herpud1 silence through restraining JNK/AP1 pathway. Collectively, our study demonstrates that Herpud1 deficiency could reduce Aβ40 expression, thereby suppressing Hcy-induced atherosclerosis by blocking the JNK/AP1 pathway. This may provide novel potential targets for atherosclerosis prevention or treatment.

Topics: Amyloid beta-Peptides; Animals; Atherosclerosis; Cells, Cultured; Homocysteine; Human Umbilical Vein Endothelial Cells; Humans; Male; MAP Kinase Signaling System; Membrane Proteins; Mice; Mice, Inbred C57BL; Peptide Fragments

Amyloid-β (Aβ) plays a crucial role in the onset and progression of atherosclerosis. Macrophages are a source of matrix metalloproteinases (MMPs), cysteine proteases and transforming growth factor (TGF)-β1 in the vascular wall. The aims of this study were to analyze the capacity of Aβ peptide (1-40) (Aβ40), Aβ peptide (1-42) (Aβ42) and fibrillar Aβ42 (fAβ42) to modulate the expression and activity of MMP-9, MMP-2 and tissue inhibitor of MMP-1 (TIMP-1) in human monocyte-derived macrophages (HMDM). Additionally, we analyzed whether Aβ internalization alters the secretion of cathepsin S (CatS) and TGF-β1 by macrophages.. HMDM were exposed to native and fibrillar Aβ. MMPs and TIMP-1 expression was analyzed by real-time PCR, and MMP abundance by zymography. Protein levels of precursor and active forms of CatS were analyzed by Western blot and TGF-β1 levels by ELISA.. Aβ40, Aβ42 and especially fAβ42 strongly induced MMP-9/MMP-2 levels. Moreover, we showed enhanced active CatS and reduced TGF-β1 protein levels in the secretome of Aβ42 and fAβ42-exposed macrophages.. Aβ can regulate the proinflammatory state of human macrophages by inducing metallo- and cysteine protease levels and by reducing TGF-β1 secretion. These effects may be crucial in atherosclerosis progression.

Topics: Amyloid beta-Peptides; Atherosclerosis; Cathepsins; Cells, Cultured; Focal Adhesion Kinase 2; Gene Expression Regulation, Enzymologic; Humans; Macrophages; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Peptide Fragments; Phosphorylation; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1