scholarly journals A Switch from Cell-Associated to Soluble PDGF-B Protects against Atherosclerosis, despite Driving Extramedullary Hematopoiesis

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1746
Author(s):  
Renée J. H. A. Tillie ◽  
Thomas L. Theelen ◽  
Kim van Kuijk ◽  
Lieve Temmerman ◽  
Jenny de Bruijn ◽  
...  
Keyword(s):  
Microvessel Density ◽  
Body Weight Gain ◽  
Oxidized Ldl ◽  
Mesenchymal Cell ◽  
Extramedullary Hematopoiesis ◽  
Collagen Content ◽  
Metabolic Effects ◽  
Intraplaque Hemorrhage ◽  
High Cholesterol Diet ◽  
Genetic Ablation

Platelet-derived growth factor B (PDGF-B) is a mitogenic, migratory and survival factor. Cell-associated PDGF-B recruits stabilizing pericytes towards blood vessels through retention in extracellular matrix. We hypothesized that the genetic ablation of cell-associated PDGF-B by retention motif deletion would reduce the local availability of PDGF-B, resulting in microvascular pericyte loss, microvascular permeability and exacerbated atherosclerosis. Therefore, Ldlr-/-Pdgfbret/ret mice were fed a high cholesterol diet. Although plaque size was increased in the aortic root of Pdgfbret/ret mice, microvessel density and intraplaque hemorrhage were unexpectedly unaffected. Plaque macrophage content was reduced, which is likely attributable to increased apoptosis, as judged by increased TUNEL+ cells in Pdgfbret/ret plaques (2.1-fold) and increased Pdgfbret/ret macrophage apoptosis upon 7-ketocholesterol or oxidized LDL incubation in vitro. Moreover, Pdgfbret/ret plaque collagen content increased independent of mesenchymal cell density. The decreased macrophage matrix metalloproteinase activity could partly explain Pdgfbret/ret collagen content. In addition to the beneficial vascular effects, we observed reduced body weight gain related to smaller fat deposition in Pdgfbret/ret liver and adipose tissue. While dampening plaque inflammation, Pdgfbret/ret paradoxically induced systemic leukocytosis. The increased incorporation of 5-ethynyl-2′-deoxyuridine indicated increased extramedullary hematopoiesis and the increased proliferation of circulating leukocytes. We concluded that Pdgfbret/ret confers vascular and metabolic effects, which appeared to be protective against diet-induced cardiovascular burden. These effects were unrelated to arterial mesenchymal cell content or adventitial microvessel density and leakage. In contrast, the deletion drives splenic hematopoiesis and subsequent leukocytosis in hypercholesterolemia.

Abstract 5553: Hypercholesterolemia Induced Overexpression of Caveolin-1 and LOX-1 Downregulates HO-1/HSP-90 Mediated e-NOS Activation: A Novel Therapeutic Strategy for the Improvement of Left Ventricular Function

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Suresh Varma Penumathsa ◽  
Srikanth Koneru ◽  
Gautam Maulik ◽  
Nilanjana Maulik
Keyword(s):  
Ventricular Remodeling ◽  
Oxidized Ldl ◽  
Immunohistochemical Analysis ◽  
Left Ventricular ◽  
Normal Diet ◽  
High Cholesterol Diet ◽  
Internal Diameter ◽  
Over Expression ◽  
Caveolin 1 ◽  
Hsp 90

Hypercholesterolemia (HC) related decrease in eNOS phosphorylation & endothelial dysfunction may account for impaired angiogenesis and subsequent increased ventricular remodeling. Over expression of Caveolin-1 (Cav-1) and Lectin-like oxidized LDL receptor (LOX-1) has been demonstrated during HC but the mechanism needs to be elucidated. To investigate this we randomized the rats into control (normal diet) and HC (5% high cholesterol diet for 8 weeks). The cholesterol, triglycerides & LDL levels were increased & the HDL levels decreased in HC compared to control. After the experimental diet period the rats were subjected to Left Anterior Descending Artery (LAD) ligation. We evaluated the expression of Cav-1, LOX-1, Heme Oxygenase (HO-1), HSP-90, phospho(p)-Akt & p-eNOS in HC and control. Significant increase in Cav-1, LOX-1 (2, 1.8 fold) & decrease in HO-1, HSP-90, p-Akt, p-eNOS & VEGF (0.5, 0.6, 0.4, 0.5 & 0.6 fold) was observed in HC compared to control. The LV functional reserve was evaluated by measuring the ejection fraction (EF), fractional shortening (FS) & LV internal diameter (LVID) after 30 days of LAD ligation. Significant increase in LVID ( 8.6 vs 7) and decrease in EF (39 vs 53%), FS (20 vs 28%), LVID (2 vs 2.7mm) as well as capillary (1888 vs 2424) & arteriolar density (1.5 vs 2.5) counts/mm2 was observed in HC compared to control. Earlier we have reported that over expression of HO-1 mediates eNOS activation & cardioprotection in MI model. To investigate the mechanism involved in HO-1 mediated cardioprotection we generated cardiac specific HO-1 over expressed transgenic (Tg) mice. Immunohistochemical analysis of HO-1 Tg mice has clearly demonstrated decreased Cav-1-eNOS interaction. Immunoblot analysis has shown to decrease Cav-1 (0.6 fold) & increased HSP-90, p-Akt, p-eNOS & VEGF expression (1.5, 1.6, 1.4 & 1.5 fold) as compared to control. These findings demonstrated that HO-1 over expression regulates HSP-90 & Cav-1 for eNOS activation. In conclusion, we demonstrate a novel mechanism of HO-1/HSP-90 mediated Cav-1-eNOS regulation leading to increased neovascularization & reduced ventricular remodeling during HC for the regression of clinical complications which would be crucial for cardiovascular drug therapy.

Bimatoprost promotes satiety and attenuates body weight in rats fed standard or obesity-promoting diets.

2020 ◽  
Author(s):  
Clayton Spada ◽  
Chau Vu ◽  
Iona Raymond ◽  
Warren Tong ◽  
Chia-Lin Chuang ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Gastric Emptying ◽  
Food Intake ◽  
Visceral Fat ◽  
Body Weight Gain ◽  
Metabolic Effects ◽  
Sprague Dawley ◽  
Hormone Levels ◽  
Gut Hormone

Abstract Background Bimatoprost negatively regulates adipogenesis in vitro and likely participates in a negative feedback loop on anandamide-induced adipogenesis. Here, we investigate the broader metabolic effects of bimatoprost action in vivo in rats under both normal state and obesity-inducing conditions. Methods Male Sprague Dawley rats were a fed standard chow (SC) diet in conjunction with dermally applied bimatoprost treatment for a period of 9–10 weeks. Body weight gain, energy expenditure, food intake, and hormones associated with satiety were measured. Gastric emptying was also separately evaluated. In obesity-promoting diet studies, rats were fed a cafeteria diet (CAF) and gross weight, fat accumulation in SQ, visceral fat and liver was evaluated together with standard serum chemistry. Results Chronic bimatoprost administration attenuated weight gain in rats fed either standard or obesity-promoting diets over a 9–10 weeks. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Additionally, SQ and visceral fat mass was distinctly affected by treatment. Bimatoprost increased satiety as measured by decreased food intake, gastric emptying and circulating gut hormone levels. Conclusions These findings suggest that bimatoprost (and possibly prostamide F2α) regulates energy homeostasis through actions on dietary intake. These actions likely counteract the metabolic actions of anandamide through the endocannabinoid system potentially revealing a new pathway that could be exploited for therapeutic development.

scholarly journals Genetic ablation of adipocyte PD-L1 reduces tumor growth but accentuates obesity-associated inflammation

2020 ◽  
Vol 8 (2) ◽  
pp. e000964 ◽  
Author(s):  
Bogang Wu ◽  
Huai-Chin Chiang ◽  
Xiujie Sun ◽  
Bin Yuan ◽  
Payal Mitra ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Tumor Growth ◽  
Body Weight Gain ◽  
High Body Mass Index ◽  
Human Adipose Tissue ◽  
Mrna Levels ◽  
Metabolic Dysfunction ◽  
Genetic Ablation ◽  
Tumor Immunosuppression

The programmed death-ligand 1 (PD-L1)-dependent immune checkpoint attenuates host immunity and maintains self-tolerance. Imbalance between protective immunity and immunopathology due to altered PD-L1 signaling can lead to autoimmunity or tumor immunosuppression. The role of the PD-L1-dependent checkpoint in non-immune system is less reported. We previously found that white adipocytes highly express PD-L1. Here we show that adipocyte-specific PD-L1 knockout mice exhibit enhanced host anti-tumor immunity against mammary tumors and melanoma with low or no tumor PD-L1. However, adipocyte PD-L1 ablation in tumor-free mice also exacerbates diet-induced body weight gain, pro-inflammatory macrophage infiltration into adipose tissue, and insulin resistance. Low PD-L1 mRNA levels in human adipose tissue correlate with high body mass index and presence of type 2 diabetes. Therefore, our mouse genetic approach unequivocally demonstrates a cell-autonomous function of adipocyte PD-L1 in promoting tumor growth and inhibiting antitumor immunity. In addition, our work uncovers a previously unrecognized role of adipocyte PD-L1 in mitigating obesity-related inflammation and metabolic dysfunction.

Sugary drinks, artificially sweetened beverages and cardiovascular disease in NutriNet-Santé cohort

2020 ◽  
Vol 30 (Supplement_5) ◽  
Author(s):  
E Chazelas ◽  
C Debras ◽  
L Fezeu ◽  
C Julia ◽  
S Hercberg ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Prospective Cohort ◽  
Body Weight Gain ◽  
Metabolic Effects ◽  
Current Debate ◽  
National Health Insurance System ◽  
Sweetened Beverages ◽  
Sugary Drinks ◽  
Incident Cases ◽  
Artificially Sweetened Beverages

Abstract Introduction Sugary drinks consumption has increased worldwide in recent years and evidence demonstrating their detrimental impact on cardio-metabolic health is accumulating. Artificially sweetened beverages (ASB) are marketed as a healthier alternative, but their cardio-metabolic impact is being debated in the scientific community. This study aimed to investigate the relationships between the consumption of ASB, sugary drinks and the risk of first incident cardiovascular disease (CVD) in a large prospective cohort. Methods The French NutriNet-Santé cohort was launched in 2009. Every 6 months participants are asked to fill 3 validated web-based 24-hour dietary records. All major health events reported by participants were validated based on their medical records by a committee of physicians. Data were also linked to national health insurance system and to the French national cause of specific mortality registry. For each type of beverage, 3 categories were defined as follows: non-consumers, low consumers and high consumers (separated by sex-specific median among consumers). Multi-adjusted Cox proportional hazard models with age as the primary time scale were performed. Results A total of 104,761 participants were included. During follow-up (2009-2019), 1,379 first incident cases of CVD occurred. Compared to non-consumers, higher consumers of sugary drinks had a higher risk of overall CVD (HR = 1.21, 95% CI 1.04 to 1.40, Ptrend=0.009). Higher consumers of ASB had also a significantly higher risk of CVD (HR = 1.30, 95% CI 1.00 to 1.71, Ptrend =0.04). Conclusions Both sugary drinks and ASB were similarly associated with CVD risk. The health effects of non-nutritive sweeteners is currently being debated based on contrasted epidemiological results. Mechanistic data suggests metabolic effects through gut microbiota perturbation and body weight gain. To imply a causal link, they need replication in other large-scale prospective cohort as well as further mechanistic investigations. Key messages Higher consumption of sugary drinks and ASB was associated with higher risk of CVD, suggesting that ASB might not be a healthy substitute for sugary drinks when considering cardiovascular health. These data provide additional arguments to feed the current debate on taxes, labeling and regulation of sugary and artificially sweetened beverages.

Changes in immune responses to oxidized LDL epitopes during aging in hypercholesterolemic apoE(−/−) mice

2006 ◽  
Vol 291 (6) ◽  
pp. R1644-R1650 ◽  
Author(s):  
Paul C. Dimayuga ◽  
Xiaoning Zhao ◽  
Juliana Yano ◽  
Kuang-Yuh Chyu
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Time Course ◽  
Oxidized Ldl ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Collagen Content ◽  
Aortic Sinus ◽  
Adaptive Immune

Atherosclerosis is a disease associated with aging and is subject to modulation by both the innate and adaptive immune system. The time course of age-dependent changes in immune regulation in the context of atherosclerosis has not been characterized. This study aims to describe alteration of the immune responses to oxidized LDL (oxLDL) during aging that is associated with changes in plaque size and phenotype in apoE(−/−) mice. Mice fed a Western diet were euthanized at 15–17, 36, or >52 wk of age. The descending aortas were stained for assessment of extent of atherosclerosis. Plaque lipid, macrophage, and collagen content were evaluated in aortic sinus lesions. The adaptive immune response to oxLDL was assessed using anti-malondialdehyde-oxidized LDL (MDA-LDL) and copper-oxidized LDL (Cu-oxLDL) IgG, and the innate immune response was assessed using anti-Cu-oxLDL and phosphorylcholine (PC) IgM. Aging was associated with a significant increase in plaque area and collagen content and a decrease in plaque macrophage and lipid content. MDA-LDL IgG significantly increased at 36 wk but was reduced in mice >52 wk. Cu-oxLDL IgG increased with age and IgG-apoB immune complexes were increased in the >52 wk group. Cu-oxLDL and PC IgM significantly increased with age. The expression of splenic cytokines such as IFN-γ, IL-4, and IL-10 increased with age. Our study shows a generalized increase in innate immune responses associated with progression of atherosclerosis and a less inflammatory and less lipid-containing plaque phenotype during aging. The adaptive immune response appeared to be less generalized, with a specific reduction in MDA-LDL IgG.

METABOLIC EFFECTS OF HYPERPHAGIA IN THE HYPOTHALAMIC-HYPERPHAGIC RAT

1966 ◽  
Vol 44 (4) ◽  
pp. 641-650 ◽  
Author(s):  
K. K. May ◽  
J. R. Beaton
Keyword(s):  
Spontaneous Activity ◽  
Body Weight Gain ◽  
Costal Cartilage ◽  
Metabolic Effects ◽  
Male Rats ◽  
Dynamic Phase ◽  
Static Phase ◽  
Electrolytic Lesions ◽  
Altered Thyroid

Metabolic effects of hyperphagia have been investigated in male rats in which hyperphagia was induced by bilateral, electrolytic lesions in the region of the ventromedial nuclei of the hypothalamus. In the early dynamic phase of hyperphagia, it would appear that increased body weight gain is a direct effect of increased energy intake not balanced by the observed increased spontaneous activity. In these animals increased lipogenesis (14C-acetate and 14C-glucose) and decreased lipolysis in vitro were evident with no evidence of altered thyroid function. Further, as determined by 35S incorporation in costal cartilage, the hyperphagia did not elicit an increased rate of skeletal growth. In the static phase, spontaneous activity was not increased, metabolic patterns were significantly altered in the direction of increased lipogenesis and decreased lipolysis, and there appeared to be a decreased uptake and release of 131I by the thyroid, which is suggestive of thyroid hypofunction.

scholarly journals Long-term effects of ghrelin and ghrelin receptor agonists on energy balance in rats

2008 ◽  
Vol 295 (1) ◽  
pp. E78-E84 ◽  
Author(s):  
Sabine Strassburg ◽  
Stefan D. Anker ◽  
Tamara R. Castaneda ◽  
Lukas Burget ◽  
Diego Perez-Tilve ◽  
...  
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Food Intake ◽  
Energy Expenditure ◽  
Therapeutic Potential ◽  
Body Weight Gain ◽  
Metabolic Effects ◽  
Positive Energy ◽  
High Dose ◽  
Growth Hormone Secretagogue

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), is the only circulating agent to powerfully promote a positive energy balance. Such action is mediated predominantly by central nervous system pathways controlling food intake, energy expenditure, and nutrient partitioning. The ghrelin pathway may therefore offer therapeutic potential for the treatment of catabolic states. However, the potency of the endogenous hormone ghrelin is limited due to a short half-life and the fragility of its bioactivity ensuring acylation at serine 3. Therefore, we tested the metabolic effects of two recently generated GHS-R agonists, BIM-28125 and BIM-28131, compared with ghrelin. All agents were administered continuously for 1 mo in doses of 50 and 500 nmol·kg−1·day−1 using implanted subcutaneous minipumps in rats. High-dose treatment with single agonists or ghrelin increased body weight gain by promoting fat mass, whereas BIM-28131 was the only one also increasing lean mass significantly. Food intake increased during treatment with BIM-28131 or ghrelin, whereas no effects on energy expenditure were detected. With the lower dose, only BIM-28131 had a significant effect on body weight. This also held true when the compound was administered by subcutaneous injection three times/day. No symptoms or signs of undesired effects were observed in any of the studies or treated groups. These results characterize BIM-28131 as a promising GHS-R agonist with an attractive action profile for the treatment of catabolic disease states such as cachexia.

PYY(3–36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity

2006 ◽  
Vol 291 (2) ◽  
pp. R367-R375 ◽  
Author(s):  
Niels Vrang ◽  
Andreas Nygaard Madsen ◽  
Mads Tang-Christensen ◽  
Gitte Hansen ◽  
Philip Just Larsen
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Peptide Yy ◽  
Body Weight Gain ◽  
Subcutaneous Administration ◽  
Treated Group ◽  
Metabolic Effects ◽  
Male Rats ◽  
Reduced Body ◽  
Gut Hormone

The gut hormone peptide YY (PYY) was recently proposed to comprise an endogenous satiety factor. We have studied acute anorectic functions of PYY(3–36) in mice and rats, as well as metabolic effects of chronic PYY(3–36) administration to diet-induced obese (DIO) mice and rats. A single intraperitoneal injection of PYY(3–36) inhibited food intake in mice, but not in rats. We next investigated the effects of increasing doses (100, 300, and 1,000 μg·kg−1·day−1) of PYY(3–36) administered subcutaneously via osmotic minipumps on food intake and body weight in DIO C57BL/6J mice. Whereas only the highest dose (1,000 μg·kg−1·day−1) of PYY(3–36) significantly reduced food intake over the first 3 days, body weight gain was dose dependently reduced, and on day 28 the group treated with 1,000 μg·kg−1·day−1 PYY(3–36) weighed ∼10% less than the vehicle-treated group. Mesenteric, epididymal, retroperitoneal, and inguinal fat pad weight was dose dependently reduced. Subcutaneous administration of PYY(3–36) (250 and 1,000 μg·kg−1·day−1) for 28 days reduced body weight and improved glycemic control in glucose-intolerant DIO rats. Neither 250 nor 1,000 μg/kg PYY(3–36) elicited a conditioned taste aversion in male rats.

scholarly journals Pyrogallol-Phloroglucinol-6 6-Bieckol on Attenuates High-Fat Diet-Induced Hypertension by Modulating Endothelial-to-Mesenchymal Transition in the Aorta of Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Myeongjoo Son ◽  
Seyeon Oh ◽  
Ji Tae Jang ◽  
Kuk Hui Son ◽  
Kyunghee Byun
Keyword(s):  
Endothelial Cells ◽  
High Fat Diet ◽  
Oxidized Ldl ◽  
Intima Media Thickness ◽  
Mesenchymal Cell ◽  
High Fat ◽  
Mesenchymal Transition ◽  
Induced Hypertension ◽  
Endothelial To Mesenchymal Transition

Endothelial-to-mesenchymal transition (EndMT), which is involved in the development of various cardiovascular diseases, is induced by dyslipidemia or obesity. In dyslipidemia, the increased levels of oxidized low-density lipoproteins (oxLDL) upregulated the lectin-type oxidized LDL receptor 1 (Lox-1), which then upregulated the down signaling pathways of PKC-α/MMPs/TGF-β/SMAD2 or 3 and increased the EndMT. In this study, we investigated the effect of pyrogallol-phloroglucinol-6,6-bieckol (PPB), which is a compound of Ecklonia cava (E. cava), on decreased blood pressure (BP) by attenuating the EndMT in a high-fat diet- (HFD-) fed animal model. We also investigated PPB’s attenuation effect on EndMT in oxLDL-treated mouse endothelial cells as an in vitro model. The results indicated that, in the aorta or endothelial cells of mice, the HFD or oxLDL treatment significantly increased the expression of Lox-1/PKC-α/MMP9/TGF-β/SMAD2/SMAD3. The PPB treatment significantly decreased its expression. In contrast, the HFD or oxLDL treatment significantly decreased the expression of the EC markers (PECAM-1 and vWF) while the PPB treatment significantly increased them. Moreover, the HFD or oxLDL treatment significantly increased the expression of the mesenchymal cell markers (α-SMA and vimentin) while PPB treatment significantly decreased them. PPB decreased the intima-media thickness and extracellular matrix amount of the aorta and attenuated the BP, which was increased by the HFD. In conclusion, PPB attenuated the upregulation of Lox-1/PKC-α/MMP9/TGF-β/SMAD2 and 3 and restored the EndMT in HFD-fed animals. Moreover, PPB showed a restoring effect on HFD-induced hypertension.

Abstract 1143: Imaging of Vasa Vasorum in Atherosclerotic Plaque with 99m Tc-labeled single chain-VEGF

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoru Ohshima ◽  
Shinichiro Fujimoto ◽  
Sotirios Tsimikas ◽  
Frank D Kolodgie ◽  
Renu Virmani ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Ex Vivo ◽  
Imaging Modality ◽  
Atherosclerotic Lesion ◽  
Vasa Vasorum ◽  
Intraplaque Hemorrhage ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Single Chain

Introduction: Adventitial vasa vasorum proliferation and neointimal neovascularization are associated with intraplaque hemorrhage, expansion of necrotic core and hence plaque vulnerability. Increased expression of VEGF and its receptors accompany neoangiogenic process. We used 99m Tc -labeled single chain VEGF (TcV) for developing potentially noninvasive imaging modality in experimentally induced aortic atherosclerotic lesion. Methods : Noninva-sive radionuclide imaging was performed with TcV (6.85 ±0. 27 mCi) in 6 NZW rabbits receiving high cholesterol diet (0.2% cholesterol, 4% fat) for one year and compared with 3 control rabbits receiving normal rabbit chow. Four hours after intravenous administration of TcV, micro SPECT/microCT imaging was performed for in vivo localization of tracer activity. Aortas were then explanted, and gamma counted for determination of % injected dose per gram (%ID/g). The aortas were then submitted for histopathologic characterization. Results : The uptake in thoracic aorta was clearly visualized non-invasively by TcV in vivo imaging in 4 of 5 rabbits in hypercholesterolemic rabbits, but not in the control animals. The %ID/g of each parts of aorta in hypercholesterolemic rabbits (Arch : 0.036 ± 0.020 %, Thoracic : 0.026 ± 0.012 %, Abd : 0.019 ± 0.009 %) was about 2.5-fold higher than that in control group (Arch : 0.014 ± 0.004 %, Thoracic : 0.009 ± 0.003 %, Abd : 0.009 ± 0.003 %) (figure a ). Ex vivo images of each group are shown as figure b . Conclusions : This preliminary study suggests a potentially novel strategy for non-invasive imaging of neoangiogenesis in atherosclerotic plaque and may allow identification of unstable plaques.

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