Search

Introduction: Measures of cardiac structure and function provide important diagnostic and prognostic information for heart failure (HF). Few studies have assessed the associations of circulating metabolites with cardiac structure and function. Hypothesis: We hypothesize that circulating metabolites that reflect aging process are associated with cardiac structure and function measures and incident HF. Methods: Participants from the Atherosclerosis Risk in Communities (ARIC) study visit 5 and the Hispanic Community Health Study / Study of Latinos (HCHS/SOL) study visit 1 who had serum metabolite measures but not prevalent HF were included. Linear regressions were used to examine the associations of metabolites with ten cardiac structure and function variables adjusting for clinical risk factors in each race and study strata, followed by random-effect meta-analyses. The Cox regression was applied to examine the relationship between those identified metabolites and incident HF post visit 5 in ARIC. Results: Among 589 analyzed metabolites, 179 were associated with cardiac structure or function measures in 706 Blacks, 3,358 Whites, and 1,380 Hispanics (FDR < 0.05). Forty-one metabolites were related to two or more measures, where 22 were associated with incident HF (308 HF cases, p Conclusions: We identified multiple metabolites associated with cardiac structure and function measures in multi-ethnic populations, highlighting metabolic pathways in aging and their impact on HF.

The roles of long non-coding RNA (LncRNA) have been highlighted in various development processes including congenital heart defects (CHD). Here, we characterized the molecular function of LncRNA, Moshe (1010001N08ik-203), one of the Gata6 antisense transcripts located upstream of Gata6, which is involved in both heart development and the most common type of congenital heart defect, atrial septal defect (ASD). During mouse embryonic development, Moshe was first detected during the cardiac mesoderm stage (E8.5 to E9.5) where Gata6 is expressed and continues to increase at the atrioventricular septum (E12.5), which is involved in ASD. Functionally, the knock-down of Moshe during cardiogenesis caused significant repression of Nkx2.5 in cardiac progenitor stages and resulted in the increase in major SHF lineage genes, such as cardiac transcriptional factors (Isl1, Hand2, Tbx2), endothelial-specific genes (Cd31, Flk1, Tie1, vWF), a smooth muscle actin (a-Sma) and sinoatrial node-specific genes (Shox2, Tbx18). Chromatin Isolation by RNA Purification showed Moshe activates Nkx2.5 gene expression via direct binding to its promoter region. Of note, Moshe was conserved across species, including human, pig and mouse. Altogether, this study suggests that Moshe is a heart-enriched lncRNA that controls a sophisticated network of cardiogenesis by repressing genes in SHF via Nkx2.5 during cardiac development and may play an important role in ASD.

TMEM100 is identified as a downstream gene of bone morphogenetic protein 9 (BMP9) signaling via activin receptor-like kinase 1 (ALK1), which is known to participate in lymphangiogenesis as well as angiogenesis. TMEM100 has been shown to be important for blood vessel formation and maintenance, but its role in the development of lymphatic vasculature remains unknown. The objective is to investigate the role of TMEM100 in development of the lymphatic system. Global Tmem100 gene deletion was induced by tamoxifen on 10.5 days post-coitus. Tmem100-inducible knockout (iKO) embryos in embryonic days (E)14.5–16.5 exhibited edema and blood-filled enlarged lymphatics with misconnections between veins and lymphatic vessels. For a reciprocal approach, we have generated a novel mouse line in which TMEM100 overexpression (OE) can be induced in endothelial cells by intercrossing with Tie2-Cre driver. TMEM100-OE embryos at E12.5–14.5 exhibited edema with small size and number of lymphatic vessels, the exact opposite phenotypes of Tmem100-iKOs. In Tmem100-iKO embryos, the number of progenitors of lymphatic endothelial cells (LECs) in the cardinal vein was increased, while it was decreased in TMEM100-OE embryos. The activity of NOTCH signaling, which limits the number of progenitors of LECs in the cardinal vein, was decreased in Tmem100-iKO embryos, whereas it was increased in TMEM100-OE embryos. TMEM100 plays an important role in the specification of LECs in the cardinal veins, at least in part, by regulating the NOTCH signaling.

Proper functioning of the lymphatic system is required for normal immune responses, fluid balance, and lipid reabsorption. Multiple regulatory mechanisms are employed to ensure the correct formation and function of lymphatic vessels; however, the epigenetic modulators and mechanisms involved in this process are poorly understood. Here, we assess the regulatory role of mouse Dot1l, a histone H3 lysine (K) 79 (H3K79) methyltransferase, in lymphatic formation. Genetic ablation of Dot1l in Tie2(+) endothelial cells (ECs), but not in Lyve1(+) or Prox1(+) lymphatic endothelial cells (LECs) or Vav1(+) definitive hematopoietic stem cells, leads to catastrophic lymphatic anomalies, including skin edema, blood–lymphatic mixing, and underdeveloped lymphatic valves and vessels in multiple organs. Remarkably, targeted Dot1l loss in Tie2(+) ECs leads to fully penetrant lymphatic aplasia, whereas Dot1l overexpression in the same cells results in partially hyperplastic lymphatics in the mesentery. Genetic studies reveal that Dot1l functions in c-Kit(+) hemogenic ECs during mesenteric lymphatic formation. Mechanistically, inactivation of Dot1l causes a reduction of both H3K79me2 levels and the expression of genes important for LEC development and function. Thus, our study establishes that Dot1l-mediated epigenetic priming and transcriptional regulation in LEC progenitors safeguard the proper lymphatic development and functioning of lymphatic vessels.

It is well known that activated microglia produce nitric oxide (NO), which has an important role in the pathophysiology of several neurodegenerative diseases such as Alzheimer's disease. In the course of searching for novel therapeutic agents from medicinal plants against neuroinflammatory diseases, the methanolic extract of Tetrapanax papyriferus was found to have significant NO inhibitory activity in lipopolysaccharide (LPS)-stimulated BV2 microglia cells. Nine oleanane-type triterpenes, including two new compounds, epipapyriogenin C-3-O-β-d-glucopyranoside (6) and 11-O-butylpapyrioside LIIc (9), were isolated from the leaves and stems of Tetrapanax papyriferus. The structures of these compounds were elucidated with 1D- and 2D-NMR and MS data. Among these Δ(11,13) oleanane-type triterpenes, compound 3 showed significant NO inhibitory activity in BV-2 cells, reducing the LPS-induced expression of COX-2 and pro-inflammatory cytokines such as TNF-α and IL-6. Compounds 7 and 9 also showed NO inhibitory activities among the Δ(12) oleanane-type triterpene saponins. These results show that oleanane-type triterpenes isolated from T. papyriferus could be a potential natural resource of NO inhibitors used in the treatment of neurodegenerative disorders.

Activin receptor-like kinase 1 (ACVRL1; ALK1) is predominantly expressed in arterial endothelial cells and plays an important role in angiogenesis. ACVRL1 mutations cause hereditary hemorrhagic telangiectasia (HHT), a genetic vascular disorder for which the underlying mechanism is poorly understood. We have found that expression of transmembrane protein 100 (Tmem100) is downregulated in the lung of Acvrl1-deficient mice; however, its function is unknown. To elucidate the role of Tmem100 in vivo, we generated a conditional knockout allele for Tmem100 in which exon3, containing the entire coding sequence, was flanked by loxP sequences. The targeted allele also possessed a lacZ reporter cassette in intron2 for visualization of Tmem100 expression. We found that Tmem100 was predominantly expressed in arterial endothelial cells of developing embryos. The conditional and reporter allele will be a useful resource to investigate the in vivo role of Tmem100, especially in angiogenesis. genesis 48:673–378, 2010. © 2010 Wiley-Liss, Inc.

This study was designed to implement and evaluate a nutrition education program for hypertensive patients aged between 50 and over. Nutrition education consisted of four sessions and, 35 out of 51 patients completed all education sessions at the public health center. To assess program effectiveness (effectively), data about blood pressure, blood cholesterol, anthropometry, nutrition knowledge, eating behavior and dietary intake were collected before and after nutrition education. Data were analyzed using SAS package (ver. 9.2) and significant difference was evaluated by paired t-test, x2-test and Wilcoxon signed rank test. Blood cholesterol was significantly reduced from 200.7 mg/dL to 188.7 mg/dL after nutrition education, although there were not significant changes in blood pressure or blood triglyceride level. Weight (p < 0.05), % body fat (p < 0.001), BMI (p < 0.05) were significantly reduced, especially in women, after nutrition education. Nutrition knowledge was increased significantly (p < 0.05), and some eating behaviors such as ``having fruits & vegetables for snack`` and ``having brown rice, barley rice than white rice`` were improved after nutrition education (p < 0.05). Sodium intake was reduced from 3,888.9 mg/day to 3,157.4 mg/day after nutrition education (p < 0.05). Except protein and iron intakes, the nutrient intake of hypertensive patients was much below the recommended level for Koreans. Dietary intakes of most of nutrients were not significantly different between pre-test and post-test. It appeared that nutrition education for the aged hypertensive patients was effective in reducing the percentage of % body fat and BMI, increasing the nutrition knowledge and some dietary behaviors. This nutrition education can be implemented at public health centers or senior centers for hypertensive patients. (Korean J Community Nutr 16(1) : 62~74, 2011)