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IGF-1 downregulated 12/15-LOX and reduced lipid oxidation in Apoe À / À mice. Mice were fed with Western type diet and infused with human IGF-1 or with saline (control). A, Total (mouse þ human) serum IGF-1 levels. B, 12/15-LOX mRNA levels in atherosclerotic aortas. C, Serum OxLDL levels. D, Serum ApoB levels. E, Serum levels of malondialdehyde (MDA), an index of lipid oxidation.
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Objective: We have shown that insulin-like growth factor I (IGF-1) infusion in Apoe(-/-) mice decreased atherosclerotic plaque size and plaque macrophage and lipid content suggesting that IGF-1 suppressed formation of macrophage-derived foam cells. Since 12/15-lipoxygenase (12/15-LOX) plays an important role in OxLDL and foam cell formation, we hyp...
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... determine whether IGF-1 reduces formation of oxidized lipids we infused human recombinant IGF-1 (or saline, control) for 4 weeks into Apoe À/À mice fed with Western diet. Our experi- mental protocol provided a 1.4-fold increase in total (human þ mouse) serum IGF-1 levels ( Fig. 2A). IGF-1 reduced 12/ 15-LOX mRNA levels in mouse atherosclerotic aortas (by 36 ± 4%, p < 0.0005) (Fig. 2B). IGF-1 decreased serum OxLDL levels by 18% without changing total lipoprotein levels (Fig. 2C, D). IGF-1 also significantly decreased serum levels of malondialdehyde (MDA) (Fig. 2E), a general marker of lipid oxidation [15]. IGF-1 ...
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... formation of oxidized lipids we infused human recombinant IGF-1 (or saline, control) for 4 weeks into Apoe À/À mice fed with Western diet. Our experi- mental protocol provided a 1.4-fold increase in total (human þ mouse) serum IGF-1 levels ( Fig. 2A). IGF-1 reduced 12/ 15-LOX mRNA levels in mouse atherosclerotic aortas (by 36 ± 4%, p < 0.0005) (Fig. 2B). IGF-1 decreased serum OxLDL levels by 18% without changing total lipoprotein levels (Fig. 2C, D). IGF-1 also significantly decreased serum levels of malondialdehyde (MDA) (Fig. 2E), a general marker of lipid oxidation [15]. IGF-1 reduced serum 8-isoprostane levels, a marker of oxidative stress [38], however this effect did not reach ...
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... into Apoe À/À mice fed with Western diet. Our experi- mental protocol provided a 1.4-fold increase in total (human þ mouse) serum IGF-1 levels ( Fig. 2A). IGF-1 reduced 12/ 15-LOX mRNA levels in mouse atherosclerotic aortas (by 36 ± 4%, p < 0.0005) (Fig. 2B). IGF-1 decreased serum OxLDL levels by 18% without changing total lipoprotein levels (Fig. 2C, D). IGF-1 also significantly decreased serum levels of malondialdehyde (MDA) (Fig. 2E), a general marker of lipid oxidation [15]. IGF-1 reduced serum 8-isoprostane levels, a marker of oxidative stress [38], however this effect did not reach statistical significance (P ¼ 0.10) (Suppl. Fig. 2). These data demonstrate that IGF-1 ...
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... increase in total (human þ mouse) serum IGF-1 levels ( Fig. 2A). IGF-1 reduced 12/ 15-LOX mRNA levels in mouse atherosclerotic aortas (by 36 ± 4%, p < 0.0005) (Fig. 2B). IGF-1 decreased serum OxLDL levels by 18% without changing total lipoprotein levels (Fig. 2C, D). IGF-1 also significantly decreased serum levels of malondialdehyde (MDA) (Fig. 2E), a general marker of lipid oxidation [15]. IGF-1 reduced serum 8-isoprostane levels, a marker of oxidative stress [38], however this effect did not reach statistical significance (P ¼ 0.10) (Suppl. Fig. 2). These data demonstrate that IGF-1 downregulates 12/15-LOX in the atherosclerotic plaque and this effect correlates with reduced ...
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... by 18% without changing total lipoprotein levels (Fig. 2C, D). IGF-1 also significantly decreased serum levels of malondialdehyde (MDA) (Fig. 2E), a general marker of lipid oxidation [15]. IGF-1 reduced serum 8-isoprostane levels, a marker of oxidative stress [38], however this effect did not reach statistical significance (P ¼ 0.10) (Suppl. Fig. 2). These data demonstrate that IGF-1 downregulates 12/15-LOX in the atherosclerotic plaque and this effect correlates with reduced lipid oxidation. (D, E). THP-1 pre-treatment with PI3 kinase inhibitor (LY2940032) partially prevented 12/15-LOX down- regulation, however pre-treatment with ERK inhibitor (PD98059) had no effect (F, ...
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... were developed with DAB substrate kit, and counterstained with hematoxylin. Antibody speci fi city was veri fi ed by staining of serial sections with “ normal ” IgG (obtained from an unimmunized animal of the same species as the primary antibody). THP-1-derived macrophages, PBMC-derived macrophages or mouse peritoneal macrophages were plated at 1.2 Â 10 6 /ml and incubated with/without IGF-1 in F10 media (Life Technologies) supplemented with 150 ug/ml human LDL (Kalen Biomedicals). To control for lipid autooxidation, media with LDL was incubated in parallel without cells. After 48 h incubation 5 mM butylated hydroxytoluene (BHT) was added to conditioned media to prevent future lipid oxidation and samples were cleaned by centrifugation (10,000 rpm/10 min). Lipid oxidation levels were quanti fi ed with Lipid Peroxidation Microplate Assay Kit from Oxford Biomedical Research according to manufacturer's instructions. This assay as- sesses malondialdehyde (MDA) as an indicator of lipid oxidation. Brie fl y, samples were incubated with N-methyl-2-phenylindole to yield a stable chromophore with maximal absorbance at 586 nm and MDA concentrations were quanti fi ed from standard curve obtained with MDA standard (1,1,3,3-Tetramethoxypropane). Since IGF-1 potentially changes macrophage-mediated LDL uptake we normalized LDL oxidation levels to LDL amounts in the conditioned media using a human ApoB ELISA kit from Cell Biolabs. Mouse OxLDL levels in serum were quanti fi ed using a commercially available ELISA (Cloud-Clone Corp., Houston, TX) in accordance with manufacturer's instructions. Serum levels of 8-isoprostane were quanti fi ed using commercially available ELISA kit (Cayman Chemical) in accordance with manufacturer's instructions. Total RNA extraction and real-time PCR was performed as previously described [2]. Brie fl y, total aortic RNA was isolated using the TriPure Isolation Reagent (Roche) followed by puri fi cation with the RNeasy mini kit (Qiagen). CDNA was synthesized using the First Strand cDNA Synthesis kit (Amersham) and used for the 40-cycle 2- step PCR with sequence-speci fi c primer pairs in the iCycler IQ Real- Time Detection System (Bio-Rad). To quantify foam cells, LDL-treated macrophages were fi xed with 4% paraformaldehyde for 10 min, washed with PBS and stained for 30 min with the neutral lipid-sensitive stain Oil Red (5 mg/ml in 60% isopropanol). After a short wash with 60% isopropanol and PBS, macrophages were imaged with an Olympus microscope and Oil Red was extracted by 100% isopropanol (10 min on a shaker) and absorbance was read at 571 nm with a microplate reader. Levels of pro-in fl ammatory cytokines were quanti fi ed with Human In fl ammatory Cytokines Multi-Analyte ELISArray kit (Qiagen, Valencia, CA) in accordance with manufacturer's instructions. All numerical data are expressed as mean ± SEM. Two-tailed unpaired Student t tests were performed to determine statistical signi fi cance. Differences were considered signi fi cant at P < 0.05. We have demonstrated previously that chronic IGF-1 infusion in Apoe À / À mice reduced atherosclerotic burden [11]. Atherosclerotic plaque from IGF-1-infused mice had decreased macrophage levels and reduced plaque lipids compared to saline-infused mice (control) [11] indicating that IGF-1 suppressed macrophage-derived foam cells. 12/15-LOX is the major pro-atherogenic enzyme mediating the formation of oxidized lipids (such as oxidized low density lipoprotein, OxLDL) [3]. We quanti fi ed plaque 12/15-LOX levels in IGF-1- and saline-infused Apoe À / À mice fed with Western diet for 12 weeks. 12/15-LOX immunopositivity was strongly detected only in the plaque cap and shoulder area (Fig. 1A). 12/15-LOX immunopositivity was mainly co-localized with macrophage marker indicating that macrophages are the major source of 12/15-LOX in the plaque (Suppl. Fig. 1). IGF-1-infused mice had a signi fi cant 67 ± 6% reduction in plaque 12/15-LOX expression compared to control (Fig. 1B). The decrease in 12/15-LOX levels induced by IGF-1 was larger than the IGF-1-promoted reduction in plaque size and in macrophage content [11], suggesting that 12/15-LOX downregulation was not secondary to these effects. To determine whether IGF-1 reduces formation of oxidized lipids we infused human recombinant IGF-1 (or saline, control) for 4 weeks into Apoe À / À mice fed with Western diet. Our experi- mental protocol provided a 1.4-fold increase in total (human þ mouse) serum IGF-1 levels (Fig. 2A). IGF-1 reduced 12/ 15-LOX mRNA levels in mouse atherosclerotic aortas (by 36 ± 4%, p < 0.0005) (Fig. 2B). IGF-1 decreased serum OxLDL levels by 18% without changing total lipoprotein levels (Fig. 2C, D). IGF-1 also signi fi cantly decreased serum levels of malondialdehyde (MDA) (Fig. 2E), a general marker of lipid oxidation [15]. IGF-1 reduced serum 8-isoprostane levels, a marker of oxidative stress [38], however this effect did not reach statistical signi fi cance (P 1⁄4 0.10) (Suppl. Fig. 2). These data demonstrate that IGF-1 downregulates 12/15-LOX in the atherosclerotic plaque and this effect correlates with reduced lipid oxidation. To further study mechanisms, human THP-1 macrophages were exposed to 0 e 100 ng/ml IGF-1 for 6 h and 12/15-LOX gene expression was analyzed by RT-PCR. IGF-1 signi fi cantly reduced 12/ 15-LOX mRNA levels by 48 ± 7% (50 ng/ml) and 55 ± 6% (100 ng/ml) (Fig. 3A). IGF-1 (50 ng/ml, 16 h) signi fi cantly reduced 12/15-LOX protein expression by 76 ± 6% (n 1⁄4 9) in THP-1 macrophages as quanti fi ed by immunoblotting with 12/15-LOX antibody (Fig. 3B,C). Treatment with IGF-1 also markedly downregulated 12/15-LOX in human PBMC-derived macrophages (by 83 ± 16%, P < 0.05, Fig. 3D,E). Since PI3 kinase- and/or ERK-dependent pathways mediate IGF-1-induced intracellular signaling [10], we tested the effects of PI3 kinase (LY2940032, 50 uM) and ERK (PD98059, 50 uM) inhibitors on IGF-1-induced 12/15-LOX downregulation. We found that pre-treatment of THP-1 macrophages with PI3 kinase inhibitor (n 1⁄4 4) but not with ERK inhibitor (n 1⁄4 4) partially prevented the decrease in 12/15-LOX induced by IGF-1 (Fig. 3F,G). These data demonstrate that a PI3 kinase-mediated pathway is involved in IGF-1's effect on 12/15-LOX expression. It has been shown that IL-4 upregulates 12/15-LOX in human monocytes and in murine macrophages via an increase in expression of signal transducer and activator of transcription 6 (STAT6) [16,17]. IL-4- induced STAT6 activation involves phosphorylation of Tyr641; however, unphosphorylated STAT6 is also able to regulate gene expression via association with p300 activation factor [18 e 20]. We hypothesized that IGF-1 downregulates macrophage 12/15-LOX via a STAT6-dependent mechanism. We found that IGF-1 downregulates STAT6 protein expression in THP-1 macrophages (Fig. 4A). Treatment with IGF-1 for 6 e 18 h did not change STAT6 gene expression levels (Suppl. Fig. 3) suggesting that a posttransciptional mechanism was responsible for STAT6 downregulation by IGF-1. A brief time treatment with IL-4 (30 min) induces STAT6 phosphorylation, however macrophage treatment with IGF-1 did not induce this effect (Suppl. Fig. 3B). To demonstrate that IGF-1- induced STAT6 downregulation is suf fi cient to reduce 12/15-LOX expression, we used STAT6-speci fi c siRNA. A/STAT6 siRNA induced a 65% reduction in STAT6 protein levels and this effect correlated with a signi fi cant downregulation of 12/15-LOX (Fig. 4B). Taken together these data suggest that IGF-1 downregulates 12/15- LOX in THP-1 macrophages, at least in part via a PI3 kinase- dependent and STAT6-mediated mechanism. To determine whether IGF-1-induced downregulation of 12/15- LOX led to suppression of macrophage-mediated lipid oxidation, IGF-1-treated THP-1 macrophages or control cells were incubated with LDL (150 ug/ml for 48 h) and lipid oxidation levels were assessed by measuring TBARS in conditioned media with data normalization to LDL amounts in the media. We found that THP-1 macrophages time-dependently increased LDL oxidation with a peak at 40 e 48 h and maximal lipid internalization at this time point occurred with 150 ug/ml LDL (data not shown). We found that IGF-1-treated THP-1 macrophages had reduced ability to oxidize lipids: LDL incubated with IGF-1-treated cells had a 65 ± 4% decrease in oxidation levels compared to LDL incubated with un- treated macrophages (Fig. 5A). Similarly, IGF-1 markedly suppressed LDL oxidation (79 ± 14% decrease, P < 0.05) induced by human PBMC-derived macrophages (Fig. 5B). Since LDL oxidation increases LDL uptake by macrophages (i.e. formation of foam cells) [21], we measured foam cell formation in IGF-1-treated or control THP-1 macrophages after incubation with LDL (Fig. 5C,D). IGF-1 reduced macrophage lipid internalization by 64 ± 4% (P < 0.001). These data demonstrate that IGF-1-induced 12/ 15-LOX downregulation was associated with a reduction in macrophage-mediated lipid oxidation and suppressed foam cell formation. We have reported previously that IGF-1-induced atheropro- tective effect was associated with reduced in fl ammatory response [11]. To assess IGF-1's effect on macrophage in fl ammatory pro fi le we quanti fi ed levels of 12 in fl ammatory cytokines in conditioned media of IGF-1-treated (or control) THP-1 macrophages (Table 1). IGF-1 signi fi cantly decreased expression of IL-1 b , IFN g and gran- ulocyte macrophage colony-stimulating factor (GM-CSF). These results suggest that suppression of macrophage-induced cytokines as well as 12/15-LOX downregulation contribute to reduced atherosclerotic burden in IGF-1-infused Apoe-null mice. We isolated peritoneal macrophages from 12/15-LOX-de fi cient and control (WT) mice and used these cells to test IGF-1's effect on cell-mediated lipid oxidation and foam cell formation. 12/15-LOX de fi ciency induced a dramatic reduction in cell-mediated LDL oxidation and foam cell formation (Fig. 6). IGF-1 reduced LDL ...
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Citations
... Furthermore, we revealed a nonlinear relationship between IGF-1 SDS and LDL-C, suggesting that a certain IGF-1 level should be maintained to modulate the serum LDL-C concentration. The potential mechanisms of this phenomenon can be explained as follows: IGF-1 can downregulate 12/ 15-lipoxygenase, thereby suppressing lipid oxidation [41], and decreased IGF-1 may impair the expression of genes involved in lipid catabolism and dysregulate the expression of related proteins encoding low-density lipoprotein receptors [28]. Furthermore, it was found that the level of LDL-C is decreased in children with growth hormone deficiency (GHD) as a result of rhGH replacement therapy. ...
Background
Elevated low-density lipoprotein cholesterol (LDL-C) levels in childhood have recently been found to be the strongest predictive risk factor for coronary artery disease in adulthood. There is an increased level of LDL-C in children and adolescents with short stature. However, the underlying factors associated with increased LDL-C levels in children and adolescents with short stature are unknown. In addition, the insulin-like growth factor 1 (IGF-1) level in the short-stature population is usually below the normal reference range. The aim of this study was to investigate the relationship between IGF-1 standard deviation score (IGF-1 SDS) and LDL-C level in children and adolescents with short stature.
Methods
A cross-sectional study was conducted in a single centre of China, 557 short-stature children and adolescents whose height SDS was lower than − 2 SD after adjustment for age and gender were included. The related clinical and laboratory examinations, including anthropometric parameters, lipid profiles, IGF-1 levels and the levels of other cofactors, were assessed in all participants.
Results
The univariate analysis results showed a significant negative correlation between IGF-1 SDS and LDL-C levels (P = 0.006). Furthermore, a nonlinear relationship was observed between IGF-1 SDS and LDL-C by smooth curve fitting after adjusting for possible confounders. A multivariate piecewise linear regression model revealed a significant negative correlation between IGF-1 SDS and LDL-C when the IGF-1 level was greater than − 2 SDS (β − 0.07, 95% CI -0.12, − 0.02; P = 0.006). However, we did not observe a significant relationship between IGF-1 SDS and LDL-C when the IGF-1 level was lower than − 2 SDS (β 0.08, 95% CI -0.02, 0.17; P = 0.119).
Conclusion
This study demonstrated a nonlinear relationship between IGF-1 and LDL-C independent of other potential confounding factors, suggesting that circulating IGF-1 may contribute to the regulation of LDL-C levels, thus meriting further investigation.
Electronic supplementary material
The online version of this article (10.1186/s12944-019-1062-z) contains supplementary material, which is available to authorized users.
... Diet is another environmental factor that can exert either beneficial or detrimental effects on cardiovascular diseases depending on its content of dietary components such as fibers, cholesterol, fatty acids, vitamins and antioxidant molecules[5,6]. Accumulation of LDL-cholesterol in the intima and subsequent modification into proatherosclerotic oxidized LDL (oxLDL) is one of the precipitating events in atherosclerosis, followed by lipid uptake by macrophages, endothelial activation and release of chemokines, cytokines, proteases and vasoactive molecules[4,7]. The early lesions known as fatty streaks are not clinically significant but are the precursors of more advanced lesions characterized by the accumulation of debris in the lipid-rich necrotic core and recruitment of smooth muscle cells (SMC). Plaques can become increasingly complex, may undergo calcification and ulceration and can ultimately occlude the vessel due to formation of a thrombus or rupture[3]. ...
Atherosclerosis is a disease in which atheromatous plaques develop inside arteries, leading to reduced or obstructed blood flow that in turn may cause stroke and heart attack. Rose hip is the fruit of plants of the genus Rosa, belonging to the Rosaceae family, and it is rich in antioxidants with high amounts of ascorbic acid and phenolic compounds. Several studies have shown that fruits, seeds and roots of these plants exert anti-diabetic, anti-obesity and cholesterol-lowering effects in rodents as well as humans. The aim of this study was to elucidate the mechanisms by which rose hip lowers plasma cholesterol, and to evaluate its effects on atherosclerotic plaque formation. ApoE-null mice were fed either a HFD (CTR) or HFD with rose hip supplementation (RH) for 24 weeks. At the end of the study we found that blood pressure and atherosclerotic plaques, together with oxidized LDL, total cholesterol and fibrinogen levels were markedly reduced in the RH group. Fecal cholesterol content, liver expression of Ldlr and selected reverse cholesterol transport (RCT) genes such as Abca1, Abcg1 and Scarb1 were significantly increased upon RH feeding. In the aorta, the scavenger receptor Cd36 and the pro-inflammatory Il1β genes were markedly downregulated compared to the CTR mice. Finally, we found that RH increased nitric oxide-mediated dilation of the caudal artery. Taken together these results suggest that rose hip is a suitable dietary supplement for preventing atherosclerotic plaques formation by modulating systemic blood pressure and the expression of RCT and inflammatory genes.
... Furthermore, a recent study has demonstrated that insulin-like growth factor I (IGF-1) infusion in ApoE (−/−) mice decreased atherosclerotic plaque size, as well as plaque macrophage and lipid content, via downregulation of 12/15-lipoxygenase (12/15-LOX). This mechanism may play a major role in the anti-atherosclerotic effects of IGF-1 [72]. In remarkable further support of the study by Chen et al. [7] published in this issue of Vascular Pharmacology, Dong and co-workers [24] demonstrated that chronic administration of Tempol (a potent antioxidant ) combined with AMPK activation is able to suppress oxidized and glycated LDL (HOG-LDL)–induced endoplasmic reticulum (ER) stress by inhibiting NAD(P)H oxidase–derived ROS, SERCA oxidation and atherosclerosis in ApoE−/− and ApoE −/−/AMPKα2 −/− mice fed on a high-fat diet. ...
Atherosclerosis is a progressive disease in which endothelial cell dysfunction, macrophage foam cell formation, and smooth muscle cell migration and proliferation, lead to the loss of vascular homeostasis. Oxidized low-density lipoprotein (OxLDL) may play a pre-eminent function in atherosclerotic lesion formation, even if their role is still debated. Several types of scavenger receptors (SRs) such as SR-AI/II, SRBI, CD36, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), toll-like receptors (TLRs) and others can promote the internalization of oxLDL. They are expressed on the surface of vascular wall cells (endothelial cells, macrophages and smooth muscle cells) and they mediate the cellular effects of OxLDL.
Although murine models of coronary atherosclerotic disease have been used extensively to determine mechanisms, limited new therapeutic options have emerged. Pigs with familial hypercholesterolemia (FH pigs) develop complex coronary atheromas that are almost identical to human lesions. We reported previously that insulin-like growth factor 1 (IGF-1) reduced aortic atherosclerosis and promoted features of stable plaque in a murine model. We administered human recombinant IGF-1 or saline (control) in atherosclerotic FH pigs for 6 months. IGF-1 decreased relative coronary atheroma in vivo (intravascular ultrasound) and reduced lesion cross-sectional area (postmortem histology). IGF-1 increased plaque's fibrous cap thickness, and reduced necrotic core, macrophage content, and cell apoptosis consistent with promotion of a stable plaque phenotype. IGF-1 reduced circulating triglycerides, markers of systemic oxidative stress and CXCL12 chemokine levels. We used spatial transcriptomics (ST) to identify global transcriptome changes in advanced plaque compartments and to obtain mechanistic insights into IGF-1 effects. ST analysis shows that IGF-1 suppressed FOS/FOSB factors and gene expression of MMP9 and CXCL14 in plaque macrophages, suggesting possible involvement of these molecules in IGF-1's effect on atherosclerosis. Thus, IGF-1 reduced coronary plaque burden and promoted features of stable plaque in a pig model, providing support for consideration of clinical trials.
Atherosclerosis (AS) is a vascular disease with plaque formation. Unstable plaques can be expected to result in cardiovascular disease, such as myocardial infarction and stroke. Studies have verified that long noncoding RNAs (lncRNAs) play a critical role in atherosclerotic plaque formation (APF), including MALAT1, GAS5, and H19. A ceRNA network is a combination of these two interacting processes, which regulate the occurrence and progression of many diseases. However, lncRNA-associated ceRNA network in terms of APF is limited. This study sought to discover novel potential biomarkers and ceRNA network for APF. We designed a triple network based on the lncRNA-miRNA and mRNA-miRNA pairs obtained from lncRNASNP and starBase. Differentially expressed genes (DEGs) and lncRNAs in human vascular tissues derived from the Gene Expression Omnibus database (GSE43292, GSE97210) were systematically selected and analyzed. A ceRNA network was constructed by hypergeometric test, including 8 lncRNAs, 243 miRNAs, and 8 mRNAs. APF-related ceRNA structure was discovered for the first time by combining network analysis and statistical validation. Topological analysis determined the key lncRNAs with the highest centroid. GO and KEGG enrichment analysis indicated that the ceRNA network was primarily enriched in “regulation of platelet-derived growth factor receptor signaling pathway,” “negative regulation of leukocyte chemotaxis,” and “axonal fasciculation.” A functional lncRNA, HAND2-AS1, was identified in the ceRNA network, and the main miRNA (miRNA-570-3p) regulated by HAND2-AS1 was further screened. This present study elucidated the important function of lncRNA in the origination and progression of APF and indicated the potential use of these hub nodes as diagnostic biomarkers and therapeutic targets.
Objective
IGF-1 (insulin-like growth factor 1) exerts pleiotropic effects including promotion of cellular growth, differentiation, survival, and anabolism. We have shown that systemic IGF-1 administration reduced atherosclerosis in Apoe −/ ⁻ (apolipoprotein E deficient) mice, and this effect was associated with a reduction in lesional macrophages and a decreased number of foam cells in the plaque. Almost all cell types secrete IGF-1, but the effect of macrophage-derived IGF-1 on the pathogenesis of atherosclerosis is poorly understood. We hypothesized that macrophage-derived IGF-1 will reduce atherosclerosis.
Approach and Results
We created macrophage-specific IGF-1 overexpressing mice on an Apoe ⁻ / ⁻ background. Macrophage-specific IGF-1 overexpression reduced plaque macrophages, foam cells, and atherosclerotic burden and promoted features of stable atherosclerotic plaque. Macrophage-specific IGF1 mice had a reduction in monocyte infiltration into plaque, decreased expression of CXCL12 (CXC chemokine ligand 12), and upregulation of ABCA1 (ATP-binding cassette transporter 1), a cholesterol efflux regulator, in atherosclerotic plaque and in peritoneal macrophages. IGF-1 prevented oxidized lipid-induced CXCL12 upregulation and foam cell formation in cultured THP-1 macrophages and increased lipid efflux. We also found an increase in cholesterol efflux in macrophage-specific IGF1–derived peritoneal macrophages.
Conclusions
Macrophage IGF-1 overexpression reduced atherosclerotic burden and increased features of plaque stability, likely via a reduction in CXCL12-mediated monocyte recruitment and an increase in ABCA1-dependent macrophage lipid efflux.
Introduction
The muscle is an endocrine organ controlling metabolic homeostasis. Irisin and myostatin are key myokines mediating this process. Acromegaly is a chronic disease with a wide spectrum of complications, including metabolic disturbances.
Purpose
To examine the influence of acromegaly on irisin and myostatin secretion and their contribution to metabolic profile and body composition.
Materials and Methods
In 43 patients with acromegaly and 60 controls, serum levels of irisin, myostatin, growth hormone (GH), insulin-like growth factor 1 (IGF-1), parameters of glucose, and lipid metabolism were determined. Body composition was assessed with dual-energy x-ray absorptiometry.
Results
The irisin concentration was significantly lower in patients with acromegaly compared to controls (3.91 vs. 5.09 μg/ml, p = 0.006). There were no correlations between irisin and GH/IGF-1 levels. In the study group, irisin was negatively correlated with fasting insulin (r = −0.367; p = 0.042), HOMA-IR (r = −0.510; p = 0.011), and atherogenic factors: Castelli I (r = −0.416; p = 0.005), Castelli II (r = −0.400; p = 0.001), and atherogenic coefficient (AC) (r = −0.417; p = 0.05). Irisin and myostatin concentrations were also lower in acromegalics with insulin resistance than without (2.80 vs. 4.18 μg/ml, p = 0.047; 81.46 vs. 429.58 ng/L, p = 0.018, respectively). There were no differences between study group and controls in myostatin concentration. Myostatin levels negatively correlated with GH (r = −0.306; p = 0.049), HOMA-IR (r = −0.046; p = 0.411), and insulin levels (r = −0.429; p = 0.016).
Conclusions
Decreased irisin concentrations in acromegaly may suggest impaired hormonal muscle function contributing to metabolic complications in this disorder. However, learning more about the association between myostatin and GH in acromegaly requires further studies. Nevertheless, it appears that myostatin is not critical for muscle mass regulation in acromegaly.
As one of the most common features of obesity, insulin resistance is central to the pathogenesis of the metabolic syndrome. Low insulin-like growth factor 1 (IGF-1) levels have been proven to be associated with many traditional cardiovascular risk factors, but it still remains controversial with the relationship between IGF-1 and insulin resistance. Accordingly, the main purpose of this study is to investigate the relationship between IGF-1 and insulin resistance in obese prepubertal boys. We used the whole-body insulin sensitivity index (WBISI) to represent insulin resistance. 70 obese prepubertal boys were included in the study, and the obese subjects were divided into two groups by using 1.285 as a threshold value for WBISI. Clinical examination and laboratory examinations were assessed for all participants. Among obese boys, the group of children with WBISI≤1.285 had lower IGF-1 standard deviation scores (SDS) (p=0.021) than the WBISI>1.285 group. The results of multiple linear analyses show that lg WBISI was positively correlated with IGF-1 SDS (p=0.031) after adjusting for traditional cardiovascular risk factors. IGF-1 SDS was negatively associated with insulin resistance in obese prepubertal boys, independent of other traditional cardiovascular disease risk markers.
Background and Purpose: Atherosclerosis is vascular disease of chronic inflammation and lipid disorder, which is a major cause of coronary heart disease. Foam cell formation is key progress during the atherosclerosis development. Insulin-like growth factor (IGF)-1 is a growth hormone that plays a crucial role in growth, metabolism, and homeostasis. Previous studies have demonstrated that increase in circulating IGF-1 can reduce atherosclerotic burden. However, active IGF-1 is characterized with poor tissue retention and is at a very low level in circulation system. Therefore, supplementation of exogenous IGF-1 to restore the physiological level is a promising approach to inhibit atherosclerosis. In this study, we develop a self-assembling, anti-inflammatory drug-modified peptide derived from IGF-1 to mimic IGF-1 bioactivity and simultaneously with an anti-inflammatory property for the treatment of atherosclerosis.
Methods: ApoE-/- mice were subcutaneously (s.c.) injected with the different hydrogels or natural IGF-1 protein solution per week and simultaneously fed a high-fat diet for 16 weeks. Atherosclerotic lesion formation and stability were assessed after treatment. Moreover, peritoneal macrophage and serum samples were collected to determine lipid profile and inflammatory cytokines. Concurrently, we determined the effect of bifunctional supramolecular nanofibers/hydrogel on cholesterol efflux, foam cell formation, phenotypic transformation of VSMC to macrophage-like cells, and macrophage polarization in vitro or in vivo.
Results: Bifunctional supramolecular nanofibers/hydrogel for the treatment of atherosclerosis was formed by a short peptide consisting of a tetrapeptide SSSR from C-region of growth factor IGF-1, an anti-inflammatory drug naproxen (Npx), and a powerful self-assembling D-peptide DFDF. The resulting hydrogel of Npx-DFDFGSSSR (Hydrogel 1, H1) possessed both the anti-inflammatory and IGF-1 mimicking properties, and it efficiently promoted the expression of ABCA1 and ABCG1, thereby significantly reducing cholesterol accumulation in macrophages and preventing foam cell formation. Moreover, H1 markedly inhibited the transformation of vascular smooth muscle cells (VSMCs) into macrophage-like cells which also contributed to foam cell formation. In addition, H1 significantly reduced the inflammatory response in vitro and in vivo. Most importantly, the IGF-1 mimetic peptide showed comparable performance to IGF-1 in vivo and inhibited atherosclerosis by markedly reducing lesion area and enhancing plaque stability.
Conclusions: Our study provides a novel supramolecular nanomaterial to inhibit pathological progress of atherosclerosis through regulating cholesterol efflux and inflammation, which may contribute to the development of a promising nanomedicine for the treatment of atherosclerosis in the clinic.
Background - Identification of protein biomarkers associated with incident atrial fibrillation (AF) may improve the understanding of the pathophysiology, risk prediction, and development of new therapeutics for AF. We examined the associations between 85 protein biomarkers and incident AF.
Methods - We included participants Ȧ5;50 years of age from the Framingham Heart Study Offspring and Third Generation cohorts, who had 85 fasting plasma proteins measured using Luminex xMAP platform. Hazard ratios (per 1 standard deviation increment of rank normalized biomarker [HR]) and 95% confidence intervals (CI) for incident AF were calculated using Cox regression models adjusted for age, sex, height, weight, current smoking, systolic blood pressure, diastolic blood pressure, hypertension treatment, diabetes, valvular heart disease, prevalent myocardial infarction, and prevalent heart failure. We used the False Discovery Rate to account for multiple testing.
Results - The study sample comprised 3378 participants (54% women), with mean (SD) age of 61.5 (8.4) years. In total, 401 developed AF over a mean follow-up of 12.3±3.8 years. We observed lower hazard of incident AF associated with higher mean levels of insulin-like growth factor 1 (IGF1) (HR per 1 standard deviation increment in protein level = 0.84; 95% CI, 0.76-0.93), and higher hazard of incident AF associated with higher mean levels of both insulin-like growth factor-binding protein 1 (IGFBP1) (HR = 1.24; 95% CI, 1.1-1.39) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) (HR = 1.73; 95% CI, 1.52-1.96).
Conclusions - Decreased levels of IGF1 and increased levels of IGFBP1 and NT-proBNP were associated with higher risk of incident AF.
