Background Atherosclerotic plaque vulnerability is a key feature of atheroprogression and precipitating acute cardiovascular events. Although the pivotal role of epigenetic regulation in atherosclerotic plaque destabilization is being recognized, the DNA methylation profile and its potential role in driving the progression and destabilization of atherosclerotic cardiovascular disease remains largely unknown. We conducted a genome-wide analysis to identify differentially methylated genes in vulnerable and non-vulnerable atherosclerotic lesions to understand more about pathogenesis. Results We compared genome-wide DNA methylation profiling between carotid artery plaques of patients with clinically symptomatic (recent stroke or transient ischemic attack) and asymptomatic disease (no recent stroke) using Infinium Methylation BeadChip arrays, which revealed 90,368 differentially methylated sites (FDR < 0.05, |delta beta|> 0.03) corresponding to 14,657 annotated genes. Among these genomic sites, 30% were located at the promoter regions and 14% in the CpG islands, according to genomic loci and genomic proximity to the CpG islands, respectively. Moreover, 67% displayed hypomethylation in symptomatic plaques, and the differentially hypomethylated genes were found to be involved in various aspects of inflammation. Subsequently, we focus on CpG islands and revealed 14,596 differentially methylated sites (|delta beta|> 0.1) located at the promoter regions of 7048 genes. Integrated analysis of methylation and gene expression profiles identified that 107 genes were hypomethylated in symptomatic plaques and showed elevated expression levels in both advanced plaques and ruptured plaques. The imprinted gene PLA2G7, which encodes lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), was one of the top hypomethylated genes with an increased expression upon inflammation. Further, the hypomethylated CpG site at the promoter region of PLA2G7 was identified as cg11874627, demethylation of which led to increased binding of Sp3 and expression of Lp-PLA(2) through bisulfate sequencing, chromatin immunoprecipitation assay and enzyme-linked immunosorbent assay. These effects were further enhanced by deacetylase. Conclusion Extensive DNA methylation modifications serve as a new and critical layer of biological regulation that contributes to atheroprogression and destabilization via inflammatory processes. Revelation of this hitherto unknown epigenetic regulatory mechanism could rejuvenate the prospects of Lp-PLA(2) as a therapeutic target to stabilize the atherosclerotic plaque and reduce clinical sequelae.

BACKGROUND:Despite the growing epidemic of heart failure (HF), there is limited data available to systematically compare non-cardiac comorbidities in the young-old, old-old, and oldest-old patients hospitalized for HF. The precise differences will add valuable information for better management of HF in elderly patients. METHODS:A total of 1053 patients aged 65 years or older hospitalized with HF were included in this study. Patients were compared among three age groups: (1) young-old: 65 to 74 years, (2) old-old: 75 to 84 years, and (3) oldest-old: ≥85 years. Clinical details of presentation, comorbidities, and prescribed medications were recorded. RESULTS:The mean age was 76.7 years and 12.7% were 85 years or older. Most elderly patients with HF (97.5%) had at least one of the non-cardiac comorbidities. The patterns of common non-cardiac comorbidities were different between the young-old and oldest-old group. The three most common non-cardiac comorbidities were anemia (53.6%), hyperlipidemia (45.9%), and diabetes (42.4%) in the young-old group, while anemia (73.1%), infection (58.2%), and chronic kidney disease (44.0%) in the oldest-old group. Polypharmacy was observed in 93.0% elderly patients with HF. Additionally, 29.2% patients were diagnosed with infection, and 67.0% patients were prescribed antibiotics. However, 60.4% patients were diagnosed with anemia with only 8.9% of them receiving iron repletion. CONCLUSIONS:Non-cardiac comorbidities are nearly universal in three groups but obviously differ by age, and inappropriate medications are very common in elderly patients with HF. Further treatment strategies should be focused on providing optimal medications for age-specific non-cardiac conditions.

目的:通过一项5年的随访初步探讨尾加压素Ⅱ(UⅡ)水平对非心肌梗死冠心病患者的预后判断价值,并同传统的危险评分作比较.方法:入选冠脉造影确诊冠心病的非心梗患者共84例,每年电话随访并查阅门诊病历,记录每名患者5年内的再发缺血或再次血管重建事件,心脏事件(心绞痛、心梗、心衰),脑血管事件,死亡,总事件率等.UⅡ水平＞2.8ng/ml计19例.EUROPA危险评分≥10,为高危(n=9).结果:列入统计的84例患者,全部完成9个月随访,完成5年随访75例(随访率90％),平均随访时间为4.8年,在UⅡ高水平组仅脑梗死率升高( 10.5％vs0％,P＜0.05),总事件率等未见统计学的差异(23.8％vs 18.5％).高危险评分组总事件率、死亡率均较低分组显著升高(44.6％vs26.7％,22.2％vs3.0％,P＜0.05),脑梗死及再次血管重建率虽然也增高,但无统计学差异(P＞0.05).结论:在非心肌梗死冠心病患者,基础UⅡ水平高者可能脑梗死发生率较高,其他的事件率包括总事件、死亡、再次血管重建等均未见到UⅡ的预测价值.

17β‐Estradiol (E2) is well known to interact with intracellular receptors that act as nuclear transcription factors. However, abundant evidence now indicates that E2 can also rapidly induce several nongenomic effects through signaling pathways related to cell growth, preservation, and differentiation. We studied the nongenomic effects of E2 in two human endometrial carcinoma cell lines, Ishikawa (estrogen receptor (ER) positive) and Hec‐1A (ER negative or low) by cultivating them with either E2 or its membrane‐impermeable conjugate, E2–BSA. We found that phosphorylation of Erk1/2 could be induced by either E2 or E2–BSA in Ishikawa cells. In Hec‐1A cells, only E2 was able to induce Erk1/2 phosphorylation. Although the existence of a nongenomic component to the response was indicated by the finding that it could not be completely inhibited by the ER antagonist ICI182780,and it can also be inhibited by calcium inhibitor Nifedipine partly. Phosphorylation of Akt could not be induced, either by E2 or E2–BSA, in either cell line. Both E2 and E2–BSA elicited calcium influx in Ishikawa cells. In contrast to these nongenomic effects, only E2 was able to stimulate expression of the anti‐apoptotic‐protein Bcl‐2. Taken together, these data indicate that nongenomic effects such as Erk1/2 phosphorylation and calcium influx can be initiated from the membrane in Ishikawa cell, and calcium can activate Erk1/2 phosphorylation. Except for ER, there must be other binding location of estrogen in endometrial cancer cells, and the nongenomic effects of estrogen initiated from plasma membrane by E2–BSA cannot lead to transcriptional effect of Bcl‐2 expression. J. Cell. Biochem. 106: 553–562, 2009. © 2009 Wiley‐Liss, Inc.

Summary1. Urotensin II (U‐II) is a powerful vasoconstrictor peptide that stimulates cell proliferation. However, the systemic effects of U‐II on cellular and extracellular matrix responses of vessel walls have not been investigated. The aim of the present study was to determine the effect of exogenous U‐II on arterial neointimal hyperplasia after balloon injury.2. A stenosis model of the thoracic aorta after balloon injury was established in male Wistar rats. Rats were divided into three groups (n = 5 in each): (i) uninjured; (ii) injured for 21 days; and (iii) injured and then treated with U‐II (1 nmol/kg per h) via an osmotic minipump for 21 days. Another group of rats were killed on Days 7 and 14 after balloon injury for the analysis ofin vitrocollagen synthesis and secretion with U‐II treated by [3H]‐proline incorporation and determination of [3H]‐hydroxyproline radioactivity, respectively.3. Urotensin II immunoreactivity was 1.74‐fold higher in vessels injured for 21 days than in uninjured vessels and mRNA levels of the urotensin UT receptor were upregulated by 55% following injury. After U‐II treatment, the mRNA levels of the UT receptor were further upregulated (by 40%). In addition, U‐II treatment increased the intimal area of injured aortas (13 ± 5vs7 ± 2% in group iii and ii, respectively), as well as increasing collagen content and cell proliferation. Protein levels of matrix metalloproteinase 1 were decreased in U‐II‐treated rats.In vitro, U‐II treatment increased collagen synthesis and secretion in uninjured vessels in a concentration‐dependent manner (10−10, 10−9and 10−8 mol/L U‐II), especially in injured aortas on Day 7 after injury.4. In conclusion, exogenous U‐II may upregulate mRNA levels of the UT receptor, as well as increase collagen and cell proliferation, all of which would contribute to intimal hyperplasia after angioplasty.