Moving Through Adolescence: Developmental Trajectories of African American and European American Youth. II: Method

<p>Heat map of TLR4-dependent gene expression changes induced by cotreatment with palmitate and mmLDL (A). J774 cells were stimulated with palmitate for 16h and incubated with or without mmLDL and LPS. Profiles of mRNA were determined by RNA-seq analysis (B-top). To validate RNA-seq results, independent real time PCRs were used to assess the expression of <i>Ccr5</i>, <i>Il-6</i>, <i>Csf-3</i>, <i>Il-1β</i>, and β–actin (B-bottom). The combination of palmitate and mmLDL caused an increase of mRNA expression of <i>Il-6</i>, <i>Csf-3</i>, and <i>Il-1β</i> genes (normalized to that of <i>Actb</i>). The real time PCR was conducted with technical duplicates, and the data shown represent three independent replicate experiments. *p <0.05 and **p <0.01 compared to LPS treatment without palmitate or mmLDL.</p

Macrophage polarization and acceleration of atherosclerotic plaques in a swine model

<div><p>Aims</p><p>Atherosclerosis is a well-known cause of cardiovascular disease and is associated with a variety of inflammatory reactions. However, an adequate large-animal model of advanced plaques to investigate the pathophysiology of atherosclerosis is lacking. Therefore, we developed and assessed a swine model of advanced atherosclerotic plaques with macrophage polarization.</p><p>Methods</p><p>Mini-pigs were fed a 2% high-cholesterol diet for 7 weeks followed by withdrawal periods of 4 weeks. Endothelial denudation was performed using a balloon catheter on 32 coronary and femoral arteries of 8 mini-pigs. Inflammatory proteins (high-mobility group box 1 [HMGB1] or tumor necrosis factor alpha (TNF-α) were injected via a micro-infusion catheter into the vessel wall. All lesions were assessed with angiography and optical coherence tomography and all tissues were harvested for histological evaluation.</p><p>Results</p><p>Intima/plaque area was significantly higher in the HMGB1- and TNF-α-injected groups compared to the saline-injected group (p = 0.002). CD68 antibody detection and polarization of M1 macrophages significantly increased in the inflammatory protein-injected groups (p<0.001). In addition, advanced atherosclerotic plaques were observed more in the inflammatory protein-injected groups compared with the control upon histologic evaluation.</p><p>Conclusion</p><p>Direct injection of inflammatory proteins was associated with acceleration of atherosclerotic plaque formation with M1 macrophage polarization. Therefore, direct delivery of inflammatory proteins may induce a pro-inflammatory response, providing a possible strategy for development of an advanced atherosclerotic large-animal model in a relatively short time period.</p></div

Proportion of carriers who had variants of each gene identified in 22 study subjects.

<p>With regard to <i>APOB</i>, seven subjects carried rare heterozygous variants, 17 common homozygous variants, and 14 had common heterozygous variants. Six subjects carried an <i>APOB</i> variant of unknown frequency. Conversely, with regard to <i>PCSK9</i>, three subjects carried rare heterozygous variants, 12 had common homozygous variants, and seven had common heterozygous variants. Five subjects carried <i>PCSK9</i> variants of unknown frequency.</p

Genetic variants identified in candidate genes in study subjects.

<p>Genetic variants identified in candidate genes in study subjects.</p

Genetic variants identified in candidate genes in study subjects.

<p>Genetic variants identified in candidate genes in study subjects.</p

Low plasma renin activity is an independent predictor of near-term incidence of hypertension in Asian populations

<p><i>Background</i>: Plasma renin activity is involved in the regulation of body salt content and blood pressure. However, there is a paucity of data regarding the association between low or high plasma renin activity and the development of hypertension.</p> <p><i>Method</i>: We investigated the relation of baseline plasma renin activity to increases in blood pressure and the incidence of hypertension after four years in 2,146 non-hypertensive individuals from a community-based Korean population (mean age, 50 years), 58% of whom were women. We defined an “increase in blood pressure” as an increment of systolic blood-pressure ≥ 10 mmHg or initiation of antihypertensive drugs and defined “hypertension” as a systolic blood pressure of 140 mm Hg or higher, a diastolic blood pressure of 90 mm Hg or higher, or the use of antihypertensive medications.</p> <p><i>Results</i>: After 4 years, the increase in blood pressure had increased in 27.9% of the participants, and hypertension had developed in 17.9%. After adjustment, the lowest sex-specific tertile of plasma renin activity was an independent risk factor of an elevation in blood pressure (Adjusted Odds Ratio 1.37, 95% confidence interval 1.07–1.74, p = 0.011) and hypertension (Adjusted Odds Ratio 1.84, 95% confidence interval 1.36–2.50, p < 0.001) compared to the highest sex-specific tertile. The associations between the plasma renin activity and blood-pressure outcomes were evident in adults with especially high urine sodium excretion.</p> <p><i>Conclusion</i>: Low plasma renin activity was associated with the development of hypertension in the middle-aged Asian population, especially in peoples with high sodium intake.</p

Survival and Development of Atherosclerotic Lesions in Apo E KO mice with AngII-induced atherosclerosis.

<p>A. Survival graph of Angiotensin II-induced atherosclerosis in Apo E KO mice with saline injection, AngII-infused, and AngII with sRAGE-treated groups. B. Immunohistochemistry sections of aorta (left =  ascending aorta, right =  infrarenal abdominal aorta) staining for inflammation markers (RAGE, ICAM-1, VCAM-1, and MCP-1) from Apo E KO mice saline injection and AngII-induced atherosclerotic Apo E KO mice (magnification: x10 and below RAGE data: x20). C. Decreased intensity in atherosclerotic areas of sRAGE-treated AngII-induced Apo E KO mice compared to AngII-induced Apo E KO mice (n = 7). The positive stain is expressed in arbitrary units normalized against a control. *<i>p</i><0.01, Scale bar = 200 µm.</p

Clinical characteristics of study subjects.

<p>Clinical characteristics of study subjects.</p

Rare and common variants of <i>APOB</i> and <i>PCSK9</i> in Korean patients with extremely low low-density lipoprotein-cholesterol levels

<div><p>Background</p><p>Screening of variants, related to lipid metabolism in patients with extreme cholesterol levels, is a tool used to identify targets affecting cardiovascular outcomes. The aim of this study was to examine the prevalence and characteristics of rare and common variants of <i>APOB</i> and <i>PCSK9</i> in Korean patients with extremely low low-density lipoprotein-cholesterol (LDL-C) levels.</p><p>Methods</p><p>Among 13,545 participants enrolled in a cardiovascular genome cohort, 22 subjects, whose LDL-C levels without lipid-lowering agents were ≤1 percentile (48 mg/dL) of Korean population, were analyzed. Two target genes, <i>APOB</i> and <i>PCSK9</i>, were sequenced by targeted next-generation sequencing. Prediction of functional effects was conducted using SIFT, PolyPhen-2, and Mutation Taster, and matched against a public database of variants.</p><p>Results</p><p>Eight rare variants of the two candidate genes (five in <i>APOB</i> and three in <i>PCSK9</i>) were found in nine subjects. Two subjects had more than two different rare variants of either gene (one subject in <i>APOB</i> and another subject in <i>APOB/PCSK9</i>). Conversely, 12 common variants (nine in <i>APOB</i> and three in <i>PCSK9</i>) were discovered in 21 subjects. Among all variants, six in <i>APOB</i> and three in <i>PCSK9</i> were novel. Several variants previously reported functional, including c.C277T (p.R93C) and c.G2009A (p.G670E) of <i>PCSK9</i>, were found in our population.</p><p>Conclusions</p><p>Rare variants of <i>APOB</i> or <i>PCSK9</i> were identified in nine of the 22 study patients with extremely low LDL-C levels, whereas most of them had common variants of the two genes. The common novelty of variants suggested polymorphism of the two genes among them. Our results provide rare genetic information associated with this lipid phenotype in East Asian people.</p></div

Effect of sRAGE in Rat Aorta Vascular Smooth Muscle Cells.

<p>Western blot analysis showing expression of A, RAGE inflammation receptor protein, ICAM-1, MCP-1, and TNF-α; and B, Quantitative data from panel A. Expression of RAGE, ICAM-1, MCP-1, TNF-α, and β-actin were detected by western blot. Lane 1, control; lane 2, AngII-treated for 24 hours (100 nM); lane 3, HMGB1 treated for 15 minutes (1 µg/ml); lane 4, AngII plus HMGB1; lane 5, AngII plus HMGB1 and sRAGE (0.5 µg/ml); lane 6, AngII plus HMGB1 and sRAGE (1 µg/ml); lane 7, AngII plus HMGB1 and sRAGE (2 µg/ml); lane 8, treatment with sRAGE alone at 2 µg/ml. The optical density is expressed in arbitrary units normalized against a control. Data in histograms represent mean ± SD from 3 experiments. *<i>p</i><0.01 vs control, ^†<i>p</i><0.01 vs lane 4, ^#<i>p</i><0.01 vs lane 4, ns = non-significant.</p