Epigenetic regulation of COL15A1 in smooth muscle cell replicative aging and atherosclerosis.

Smooth muscle cell (SMC) proliferation is a hallmark of vascular injury and disease. Global hypomethylation occurs during SMC proliferation in culture and in vivo during neointimal formation. Regardless of the programmed or stochastic nature of hypomethylation, identifying these changes is important in understanding vascular disease, as maintenance of a cells' epigenetic profile is essential for maintaining cellular phenotype. Global hypomethylation of proliferating aortic SMCs and concomitant decrease of DNMT1 expression were identified in culture during passage. An epigenome screen identified regions of the genome that were hypomethylated during proliferation and a region containing Collagen, type XV, alpha 1 (COL15A1) was selected by 'genomic convergence' for characterization. COL15A1 transcript and protein levels increased with passage-dependent decreases in DNA methylation and the transcript was sensitive to treatment with 5-Aza-2'-deoxycytidine, suggesting DNA methylation-mediated gene expression. Phenotypically, knockdown of COL15A1 increased SMC migration and decreased proliferation and Col15a1 expression was induced in an atherosclerotic lesion and localized to the atherosclerotic cap. A sequence variant in COL15A1 that is significantly associated with atherosclerosis (rs4142986, P = 0.017, OR = 1.434) was methylated and methylation of the risk allele correlated with decreased gene expression and increased atherosclerosis in human aorta. In summary, hypomethylation of COL15A1 occurs during SMC proliferation and the consequent increased gene expression may impact SMC phenotype and atherosclerosis formation. Hypomethylated genes, such as COL15A1, provide evidence for concomitant epigenetic regulation and genetic susceptibility, and define a class of causal targets that sit at the intersection of genetic and epigenetic predisposition in the etiology of complex disease.

Atherosclerosis, inflammation, genetics, and stem cells: 2012 update.

Atherosclerosis is a peculiar form of inflammation triggered by cholesterol-rich lipoproteins and other noxious factors such as cigarette smoke, diabetes mellitus, and hypertension. Genetics also play an important role in the disease, accounting for about 40% of the risk. Of surprise in recent years of post-human genome sequencing, atherosclerosis-relevant genes discovered by non-biased techniques (ie, genome-wide association studies), did not rehash previously suspected pathways of lipid metabolism, diabetes, or hypertension. Instead these studies highlighted genes relevant to mechanisms of inflammation and stem cell biology. Only a minority of implicated genes were linked to lipid and other cardiac risk factor genes. Although such findings do not contradict the fact that atherosclerosis is triggered and exacerbated by elevated lipids, atherosclerosis "new genes" suggest that the mechanism responsible for the development of arterial lesions is more complex than a simple response to injury, where injury is necessary, but perhaps not sufficient, for disease progression.

Notch activation induces endothelial cell senescence and pro-inflammatory response: implication of Notch signaling in atherosclerosis.

OBJECTIVE: Notch signaling plays pivotal roles in the pathogenesis of vascular disease. However, little is known about its role in atherosclerosis. We sought to investigate the potential involvement of the Notch signaling in atherosclerosis. METHODS: Expression of Notch pathway components in mouse and human aorta with or without atherosclerosis plaque was examined by immunohistochemistry. Expression of Notch target genes in young versus aged human endothelial cells (EC) was examined by PCRArray and immunoblot. In vitro loss- and gain-of-function approaches were utilized to evaluate the role of Notch signaling in inducing EC senescence and secretion of pro-inflammatory cytokines by ProteinArray. Notch gene profile was studied in 1054 blood samples of patients with coronary artery disease (CAD). Genotyping was performed using the Genome-Wide Single Nucleotide Polymorphism (SNP) Array. RESULTS: Notch pathway components were upregulated in luminal EC at atherosclerotic lesions from mouse and human aortas. In addition, the Notch pathway was activated in aged but not young human EC. Enforced Notch activation resulted in EC senescence and significantly upregulated expression of several molecules implicated in the inflammatory response (IL-6/IL-8/IL-1α/RANTES/ICAM-1). The upregulated IL-6 was partially responsible for mediating leukocyte transendothelial migration. Genetic association analysis detected, of 82 SNPs across 6 Notch pathway genes analyzed, 4 SNPs with nominal association with CAD burden. CONCLUSION: Notch pathway is activated in luminal EC at atherosclerotic plaques and results in pro-inflammatory response and senescence of EC. Notch signaling may be linked to human CAD risk. These findings implicate a potential involvement of Notch signaling in atherosclerosis.

The meaningful use of the review of symptoms in heart failure patients.

Review of symptoms (ROS) is a time-honored tradition in medicine and has proved to be a case-finding maneuver in general medicine patients. The authors sought to investigate the prevalence of noncardiovascular symptoms in heart failure clinics by assessment of the ROS. Of the collected ROS, shortness of breath (SOB) represented the most frequent recalled symptom (8.6%), whereas fatigue (5.3%) was the most common noncardiac symptom. Multivariate regression analysis revealed that New York Heart Association class could, at least in part, explain the occurrence of SOB (R(2) =.4; P<.05). Importantly, alarm symptoms such as hemoptysis and bloody stools were present in <1% of the cohort. ROS evaluation remains a valuable tool for diagnostics; however, symptom-focused questionnaires should be routinely considered as a time-efficient strategy in the ambulatory specialty clinic.

Inflammation, stem cells and atherosclerosis genetics.

Atherosclerosis and its associated complications remain the primary cause of death in humans. Aging is the main contributor to atherosclerosis, compared with any other risk factor, yet the specific manner in which age increases risk (the 'aging-risk' mechanism) remains elusive. A novel concept for atherosclerosis risk implicates a lack of endothelial progenitor cell (EPC)-dependent arterial repair in the development of the disease that is secondary to exhaustion of repair-competent EPCs. Molecular evidence derived from genetic techniques indicates atherosclerotic lesions may begin to form as arterial repair fails, rather than merely following arterial injury. Thus, chronic arterial injury may overwhelm the ability of EPCs to maintain arterial homeostasis, particularly when EPCs capable of arterial repair become exhausted. Recent studies have reported genes identified using non-biased approaches (ie, genetic linkage studies and genome-wide association studies) that are associated with susceptibility for atherosclerosis and related thromboembolic disorders; these genes may be implicated in the control of arterial wall inflammation and EPC-mediated tissue repair. Most of the genes identified by using non-biased genomic techniques are associated with inflammation, immune response and stem cells. This review focuses on new genetic data in the field of atherosclerosis and arterial homeostasis.

Of cardiovascular illness and diversity of biological response.

Noise in gene expression (stochastic variation in the composition of the transcriptome in response to stimuli) may play an important role in maintaining robustness and flexibility, which ensure the stability of normal physiology and provide adaptability to environmental changes for the living system. Broad-based technologies have allowed us to study with unprecedented accuracy the molecular profiles of various states of health and cardiovascular disease. In doing so, we have observed a correlation between the degree of variation in gene expression and the state of health. Specifically, the stochastic variation in gene expression in response to environmental and physiological factors is found in healthy mice, and tends to disappear in mice with advanced disease states. Although further evidence is needed to draw a solid conclusion with respect to the significance of decreased transcriptional noise in the disease state as a whole, it is tantalizing to introduce the concept that stochasticity may be linked to the organism's adaptability to a changing environment, and the "quiet" states of gene expression may indicate the loss of diversity in the organism's response.

Unraveling the genetics of atherosclerosis: implications for diagnosis and treatment.

The hereditary aspect of atherosclerosis has been known for some time in clinical medicine. Over the past three decades, a great deal of research has focused on defining the genetic component of this disease with the hopes that detailed knowledge of the genes and gene variants will lead to improvements in the diagnosis and treatment. This article reviews the different approaches for studying the genetics of atherosclerosis and the potential for using the results in clinical practice.