ResearchPad - vascular-disease-and-pathophysiology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-LB95 Low Density Lipoprotein Receptor and Proprotein Convertase Subtilisin/Kexin Type 9 Kinetics Using Heavy Water (2H2O) Labeling and Mass Spectrometry]]> https://www.researchpad.co/article/elastic_article_8654 Abnormally high blood cholesterol levels in low density lipoprotein (LDL) increases the risk of heart disease. Cell surface receptors such as LDL-receptors (LDLr) regulate the clearance of LDL from blood circulation. As cholesterol levels decrease, cells promote cholesterol synthesis and cholesterol uptake by increasing LDLr expression. Another regulatory protein of plasma cholesterol clearance is proprotein convertase subtilisin/kexin type 9 (PCSK9). It is secreted from the liver into circulation where it can bind to and target LDLr to the lysosome for subsequent degradation. The current model of cholesterol regulation describes how increased cholesterol content down-regulates the number of LDLr promoted by PCSK9 mediated degradation, however minimal knowledge is not known about LDLr and PCSK9 kinetics using heavy water labeling, and how cholesterol enriched diet affects LDLr and PCSK9 kinetics in vivo. Therefore, our objective(s) were to establish a method 1) to measure the kinetics of LDLr and PCSK9 via stable isotopic metabolic labeling with heavy water (2H2O) in vivo 2) to further test established models of cholesterol metabolic regulation on LDLr and PCSK9 turnover after feeding mice a cholesterol enriched diet. We hypothesize that a cholesterol enriched diet will decrease both LDLr and PCSK9 synthesis rates. In order to test this, mice were fed a cholesterol enrich diet for 1 week and metabolically labeled with heavy water (2H2O) up to 36 hours. LDLr and PCSK9 were immunoprecipitated from liver and deuterium incorporation into LDLr and PCSK9 were measured via mass spectrometry. Our results revealed high cholesterol feeding down-regulated cholesterol synthesis and LDLr fractional synthesis rate decreased from 10.0% to 6% per hour. PCSK9 concentration also decreased from 1 to 0.2 (ng/ml / total mg protein), but the synthesis rate increased from 9.0%/day in control mice to 19.5%/day in high cholesterol diet. These results suggest high cholesterol feeding increases PCSK9 synthesis that potentially depletes the intracellular pool to target LDLr to the lysosome thus decreasing LDLr turnover. This research provides a flux-based approach to measure the kinetics of LDLr and PCSK9 for a molecular based kinetic insight of their functions in physiology, disease and therapy.

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<![CDATA[SAT-LB98 Early Atherosclerosis in Polycystic Ovary Syndrome. a Systematic Review, Meta-Analysis and Meta-Regression]]> https://www.researchpad.co/article/elastic_article_5895 Backgroung. Polycystic ovary syndrome (PCOS) is a common disorder affecting reproductive age women and is a cluster of endocrine and metabolic alterations ranging from impaired ovulation and androgen excess to abdominal obesity and metabolic syndrome leading to increased cardiovascular risk profile. Aim. To perform a meta-analysis on the effect of PCOS on surrogate markers of atherosclerosis, namely intima media thickness (IMT), flow-mediated dilation (FMD) and pulse wave velocity (PWV) and to run a meta-regression on the potential determinants of preclinical atherosclerosis. Methods. A search through Pubmed/Medline and ISI-web of knowledge retrieved 90 studies that were used for meta-analysis. Selected outcomes were IMT (n=6199), FMD (n=3090), and PWV (n=2477) while age, BMI, waist circumference, total testosterone, free androgen index (FAI), total-, HDL- and LDL-cholesterol, HOMA-index, systolic and diastolic blood pressure were used for meta-regression analysis. Results. Random effect meta-analysis showed that IMT was significantly increased (ES 0.47, 95% C.I. 0.64 to 0.30, p<0.0001), FMD was significantly impaired (ES -0.92, 95% C.I. -0.69 to -1.15, p<0.0001) and PWV was significantly increased (ES 0.28, 95% C.I. 0.48 to 0.08, p=0.006) in PCOS compared to controls. Meta-regression analysis showed that FMD was positively correlated with FAI (p=0.018) while negative correlations were found between Effect Size (IMT) and BMI (p=0.02), waist circumference (p=0.05) and total cholesterol (p=0.02). Conclusions. This meta-analysis shows a clear effect of PCOS on all markers of preclinical atherosclerosis (IMT, FMD and PWV). Heterogeneity of results is explained in part by the androgen status that was positively linked to impairment of FMD while increasing of anthropometric and metabolic variables (waist, BMI and total cholesterol) seem to overcome PCOS on preclinical atherosclerosis.

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<![CDATA[SAT-LB96 Chronic Kidney Disease Incidence and Cardiorespiratory Fitness Association in Patients With Diabetes And/Or Hypertension]]> https://www.researchpad.co/article/N1c5beac1-73ab-4495-bb2f-0eda5e450d71 <![CDATA[SAT-LB97 MiRNA-99a and mTOR2 Mediate Enhanced Endothelial Mineralocorticoid Receptor Signaling-Induced Activation of Sodium Channel and Endothelium Stiffness]]> https://www.researchpad.co/article/Nebfec9f3-9334-4c59-8776-0489f15434e5 <![CDATA[SAT-LB99 Inflammation May Mediate Coronary Artery Disease in Women With Hypothalamic Hypoestrogenemia: Findings From the NHLBI-Sponsored Women’s Ischemia Syndrome Evaluation (WISE)]]> https://www.researchpad.co/article/Nc2aed64f-0156-471a-8af8-efe395e259af