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Ling Tang, Guoliang Wang, Long Jiang, Panpan Chen, Wei Wang, Juan Chen, Luya Wang
OBJECTIVES: Familial hypercholesterolemia (FH) is an autosomal dominant disorder of cholesterol metabolism. Three recognized genes (LDLR, APOB and PCSK9) present in only 20-30% of patients with possible FH cases. Additional FH-causing genes need to be explored. The present study found an isolated gene change, sEH R287Q, in a core family of FH. In this study, we aimed to investigate the roles of R287Q on sEH expression and on LDLR expression, LDL binding to LDLR and LDL internalization...
April 14, 2018: Gene
Seong H Choi, Ghazal Gharahmany, Rosemary L Walzem, Thomas H Meade, Stephen B Smith
We hypothesized that consumption of saturated fatty acids in the form of high-fat ground beef for 5 weeks would depress liver X receptor signaling targets in peripheral blood mononuclear cells (PBMC) and that changes in gene expression would be associated with the corresponding changes in lipoprotein cholesterol (C) concentrations. Older men (n = 5, age 68.0 ± 4.6 years) and postmenopausal women (n = 7, age 60.9 ± 3.1 years) were assigned randomly to consume ground-beef containing 18% total fat (18F) or 25% total fat (25F), five patties per week for 5 weeks with an intervening 4-week washout period...
April 16, 2018: Lipids
Kalyani Mondal, Pratip Chakraborty, S N Kabir
Women with polycystic ovary syndrome (PCOS) are at increased risk of cardiovascular diseases (CVD); however, the independent role of PCOS in the incident CVD remains unknown. There are reports that hyperhomocysteinemia (HHcy), a potential cause of CVD, is frequently associated with PCOS. The present study investigates the independent attributes of hyperandrogenemia (HA), the integral associate of PCOS, and HHcy in causing atherogenic dyslipidemia. Twenty-five-day old rats were treated with homocysteine (Hcy) at 50 mg/kg/day dose level for 12 weeks...
April 13, 2018: Biochemical and Biophysical Research Communications
Laura J den Hartigh, Zhan Gao, Leela Goodspeed, Shari Wang, Arun K Das, Charles F Burant, Alan Chait, Martin J Blaser
Background: trans-10,cis-12 Conjugated linoleic acid (t10,c12-CLA) is a dietary supplement that promotes weight loss by increasing fat oxidation and energy expenditure. We previously reported that in the absence of t10,c12-CLA, mice forced to lose equivalent body weight by food restriction (FR) do not exhibit increases in fat oxidation or energy expenditure but have improved glucose metabolism, consistent with FR as a metabolically healthy weight-loss method. Objective: Because diet is a primary determinant of gut bacterial populations, we hypothesized that the disparate metabolic effects accompanying weight loss from t10,c12-CLA or FR could be related to altered intestinal microbiota...
April 1, 2018: Journal of Nutrition
Aránzazu Rossignoli, Emina Vorkapic, Anders Wanhainen, Toste Länne, Josefin Skogberg, Erika Folestad, Dick Wågsäter
Atherosclerosis is the main underlying causes of cardiovascular disease. There is a well‑established association between high blood cholesterol levels and the extent of atherosclerosis. Furthermore, atherosclerosis has been proposed to augment abdominal aortic aneurysm (AAA) formation. As patients with AAA often have parallel atherosclerotic disease and are therefore often on cholesterol‑lowering therapy, it is not possible to fully address the independent effects of plasma cholesterol lowering (PCL) treatment on AAA...
April 5, 2018: International Journal of Molecular Medicine
Ruozhi Zhao, Nora Ghazzawi, Jiansu Wu, Khuong Le, Chunyang Li, Mohammed H Moghadasian, Yaw L Siow, Franklin Apea-Bah, Trust Beta, Zhengfeng Yin, Garry Shen
The present study investigated the effects of germinated brown rice (GBR) on atherosclerosis and underlying mechanism in low-density lipoprotein receptor-knockout (LDLr-KO) mice. The sizes of atherosclerotic lesions in aortic roots of LDLr-KO mice fed with diet supplemented with 60% GBR (weight/weight) were significantly less than that in mice fed with 60% of white rice (WR) or control diet (p<0.05) and all diets containing 0.06% cholesterol. WR or GBR diet did not significantly alter plasma total or LDL-cholesterol, fecal sterols, glucose or the activities of antioxidant enzymes compared to the control diet...
April 16, 2018: Journal of Agricultural and Food Chemistry
Bindu Ramachandran, John N Stabley, Su-Li Cheng, Abraham S Behrmann, Austin Gay, Li Li, Megan Mead, Julia Kozlitina, Andrew Lemoff, Hamid Mirzaei, Zhijian Chen, Dwight A Towler
In aortic vascular smooth muscle (VSM), the canonical Wnt receptor LRP6 inhibits protein arginine (Arg) methylation, a new component of noncanonical Wnt signaling that stimulates nuclear factor of activated T cells (viz., NFATc4). To better understand how methylation mediates these actions, mass spectrometry was performed on VSM cell extracts from control and LRP6-deficient mice. LRP6-dependent Arg methylation was regulated on > 500 proteins; only 21 exhibited increased monomethylation (MMA) with concomitant reductions in dimethylation...
April 6, 2018: Journal of Biological Chemistry
Daniel Engelbertsen, Marie A C Depuydt, Robin A F Verwilligen, Sara Rattik, Erik Levinsohn, Andreas Edsfeldt, Felicia Kuperwaser, Petr Jarolim, Andrew H Lichtman
BACKGROUND: Interleukin-23 (IL-23) has been implicated in inflammatory and autoimmune diseases by skewing CD4+ T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL-23 receptor (IL-23R)-expressing cells in the atherosclerotic aorta and evaluated the effect of IL-23R deficiency on atherosclerosis development in mice. METHODS AND RESULTS: We used heterozygous Ldlr -/- Il23r e GFP / WT knock-in mice to identify IL-23R-expressing cells by flow cytometry and homozygous Ldlr -/- Il23r e GFP / eGFP ( Ldlr -/- Il23r -/- ) mice to investigate the effect of lack of IL-23R in atherosclerosis...
April 4, 2018: Journal of the American Heart Association
Sheng-Hua Yang, Rui-Xia Xu, Chuan-Jue Cui, Yin Wang, Ying Du, Zhi-Guo Chen, Yu-Hong Yao, Chun-Yan Ma, Cheng-Gang Zhu, Yuan-Lin Guo, Na-Qiong Wu, Jing Sun, Bu-Xing Chen, Jian-Jun Li
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol homeostasis, is associated with glucose metabolism. Liraglutide, a glucagon-like peptide-1 receptor agonist, can increase insulin secretion in a glucose-dependent manner and lower blood glucose. We aimed to investigate the relationship between liraglutide and PCSK9. METHODS: At the cellular level, the expressions of PCSK9 and hepatocyte nuclear factor 1 alpha (HNF1α) protein in HepG2 cells stimulated by liraglutide was examined using Western blot...
April 4, 2018: Cardiovascular Diabetology
Sissel Beate Rønning, Mona Elisabeth Pedersen, Ragnhild Stenberg Berg, Bente Kirkhus, Rune Rødbotten
Skeletal muscle function is highly dependent on the ability to regenerate, however, during ageing or disease, the proliferative capacity is reduced, leading to loss of muscle function. We have previously demonstrated the presence of vitamin K2 in bovine skeletal muscles, but whether vitamin K has a role in muscle regulation and function is unknown. In this study, we used primary bovine skeletal muscle cells, cultured in monolayers in vitro, to assess a potential effect of vitamin K2 (MK-4) during myogenesis of muscle cells...
2018: PloS One
Anquan Liu, Johan Frostegård
BACKGROUND: Activated T cells and dendritic cells (DCs) occur in atherosclerotic plaques. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR), and results in increased LDL-levels. We here investigate immune effects of PCSK9 on OxLDL induced DC maturation and T cell activation. METHODS: T cells were isolated from carotid specimens of patients undergoing carotid endarterectomy, or from peripheral blood of healthy individuals. Human peripheral blood monocytes were differentiated into DCs...
April 4, 2018: Journal of Internal Medicine
Natali Baltieri, Daniele M Guizoni, Jamaira A Victorio, Ana P Davel
Background: Endothelial dysfunction plays a pivotal role in the initiation of atherosclerosis. Vascular insulin resistance might contribute to a reduction in endothelial nitric oxide (NO) production, leading to impaired endothelium-dependent relaxation in cardiometabolic diseases. Because perivascular adipose tissue (PVAT) controls endothelial function and NO bioavailability, we hypothesized a role for this fat deposit in the vascular complications associated with the initial stages of atherosclerosis. Therefore, we investigated the potential involvement of PVAT in the early endothelial dysfunction in hypercholesterolemic LDL receptor knockout mice (LDLr-KO)...
2018: Frontiers in Physiology
Tao Yu, Mengli Wang, Yadong Wen, Yingya Cao, Guanggui Shen, Xiaogan Jiang, Jingyi Wu, Weihua Lu, Xiaoju Jin
BACKGROUND: Our previous study demonstrated that ventilators increase diaphragmatic lipid accumulation in rabbits, but their cellular mechanism is poorly understood. Mammalian target of rapamycin (mTOR) plays an important role in atherosclerosis in rat vascular smooth muscle cells. The present study investigated the role of mTOR pathway activation in the diaphragmatic muscle of ventilated rats and hypoxia-induced C2C12 cells. MATERIALS AND METHODS: Male Sprague-Dawly rats were randomized into a control group (n = 8), controlled mechanical ventilation (CMV) group (n = 8), and CMV + Rapa group (n = 8)...
May 2018: Journal of Surgical Research
Youlin Wang, Weiqing Tang, Pan Yang, Hyunsu Shin, Qingwang Li
BACKGROUND AND AIMS: Niemann-Pick C1-like1 (NPC1L1), a crucial cholesterol absorption receptor expressed in human intestine and liver. But in mouse it is only expressed in intestine. Previous studies elucidated that expression of human NPC1L1 in mouse liver led to increase of plasma cholesterol due to activation of absorption from bile. However, hepatic NPC1L1 function was not elucidated in LDL receptor deficient mouse (LDLR-/-) in which LDL was a main lipoprotein as in human. METHODS AND RESULTS: L1-Tg/LDLR-/- mouse was created by crossing liver-specific NPC1L1 transgenic mouse (L1-Tg) with LDLR-/-...
March 27, 2018: Biochemical and Biophysical Research Communications
Christopher Tay, Yu-Han Liu, Peter Kanellakis, Axel Kallies, Yi Li, Anh Cao, Hamid Hosseini, Peter Tipping, Ban-Hock Toh, Alex Bobik, Tin Kyaw
OBJECTIVE: B cells promote or protect development of atherosclerosis. In this study, we examined the role of MHCII (major histocompatibility II), CD40, and Blimp-1 (B-lymphocyte-induced maturation protein) expression by follicular B (FO B) cells in development of atherosclerosis together with the effects of IgG purified from atherosclerotic mice. APPROACH AND RESULTS: Using mixed chimeric Ldlr -/- mice whose B cells are deficient in MHCII or CD40, we demonstrate that these molecules are critical for the proatherogenic actions of FO B cells...
March 29, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Samantha E Adamson, Renata Polanowska-Grabowska, Kathryn Marqueen, Rachael Griffiths, Jerry Angdisen, Sarah R Breevoort, Ira G Schulman, Norbert Leitinger
OBJECTIVE: Inflammatory macrophages promote the development of atherosclerosis. We have identified the adaptor protein Dab2 (disabled homolog 2) as a regulator of phenotypic polarization in macrophages. The absence of Dab2 in myeloid cells promotes an inflammatory phenotype, but the impact of myeloid Dab2 deficiency on atherosclerosis has not been shown. APPROACH AND RESULTS: To determine the role of myeloid Dab2 in atherosclerosis, Ldlr-/- mice were reconstituted with either Dab2-positive or Dab2-deficient bone marrow and fed a western diet...
March 29, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Shannon M Jones, Adrien Mann, Kelsey Conrad, Keith Saum, David E Hall, Lisa M McKinney, Nathan Robbins, Joel Thompson, Abigail D Peairs, Eric Camerer, Katey J Rayner, Michael Tranter, Nigel Mackman, A Phillip Owens
OBJECTIVE: PAR2 (protease-activated receptor 2)-dependent signaling results in augmented inflammation and has been implicated in the pathogenesis of several autoimmune conditions. The objective of this study was to determine the effect of PAR2 deficiency on the development of atherosclerosis. APPROACH AND RESULTS: PAR2 mRNA and protein expression is increased in human carotid artery and mouse aortic arch atheroma versus control carotid and aortic arch arteries, respectively...
March 29, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Paul Lebeau, Khrystyna Platko, Ali A Al-Hashimi, Jae Hyun Byun, Šárka Lhoták, Nicholas Holzapfel, Gabriel Gyulay, Suleiman A Igdoura, David Cool, Bernardo Trigatti, Nabil G Seidah, Richard C Austin
The proprotein convertase subtilisin/kexin type-9 (PCSK9) plays a central role in cardiovascular disease (CVD) by degrading hepatic low-density lipoprotein receptor (LDLR). As such, loss-of-function (LOF) PCSK9 variants that fail to exit the endoplasmic reticulum (ER) increase hepatic LDLR levels and lower the risk of developing CVD. The retention of misfolded protein in the ER can cause ER stress and activate the unfolded protein response (UPR); in this study, we investigated whether a variety of LOF PCSK9 variants that are retained in the ER can cause ER stress and hepatic cytotoxicity...
March 28, 2018: Journal of Biological Chemistry
Sabina Beheshti, Christian M Madsen, Anette Varbo, Marianne Benn, Børge G Nordestgaard
Background -Familial hypercholesterolemia(FH) is a condition with very high concentrations of low-density lipoprotein(LDL) cholesterol and high risk of ischemic heart disease including myocardial infarction. However, there is limited and contradictory information on whether FH and high LDL cholesterol per se confer high risk of ischemic stroke. We tested the hypotheses that individuals in the general population with FH and/or high LDL cholesterol have higher risk of ischemic stroke. Methods -The associations of FH and high LDL cholesterol with ischemic stroke risk were tested in both causal, genetic and observational analyses using 106,412 individuals from the Copenhagen General Population Study(CGPS; 2823 ischemic strokes and 3,792 myocardial infarctions) and/or 10,372 individuals from the Copenhagen City heart Study(CCHS; 945 ischemic strokes and 1,142 myocardial infarctions)...
March 28, 2018: Circulation
Sigal Kfir, Raghavendra Basavaraja, Noa Wigoda, Shifra Ben-Dor, Irit Orr, Rina Meidan
To unveil novel global changes associated with corpus luteum (CL) maturation, we analyzed transcriptome data for the bovine CL on days 4 and 11, representing the developing vs. mature gland. Our analyses revealed 681 differentially expressed genes (363 and 318 on day 4 and 11, respectively), with ≥2 fold change and FDR of <5%. Different gene ontology (GO) categories were represented prominently in transcriptome data at these stages (e.g. days 4: cell cycle, chromosome, DNA metabolic process and replication and on day 11: immune response; lipid metabolic process and complement activation)...
2018: PloS One
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