The chromosome 9p21 (Chr9p21) locus of coronary artery disease has been identified in the first surge of genome-wide association and is the strongest genetic factor of atherosclerosis known today. ...Chr9p21 encodes the long non-coding RNA (ncRNA) antisense non-coding RNA in the INK4 locus (ANRIL). ANRIL expression is associated with the Chr9p21 genotype and correlated with atherosclerosis severity. Here, we report on the molecular mechanisms through which ANRIL regulates target-genes in trans, leading to increased cell proliferation, increased cell adhesion and decreased apoptosis, which are all essential mechanisms of atherogenesis. Importantly, trans-regulation was dependent on Alu motifs, which marked the promoters of ANRIL target genes and were mirrored in ANRIL RNA transcripts. ANRIL bound Polycomb group proteins that were highly enriched in the proximity of Alu motifs across the genome and were recruited to promoters of target genes upon ANRIL over-expression. The functional relevance of Alu motifs in ANRIL was confirmed by deletion and mutagenesis, reversing trans-regulation and atherogenic cell functions. ANRIL-regulated networks were confirmed in 2280 individuals with and without coronary artery disease and functionally validated in primary cells from patients carrying the Chr9p21 risk allele. Our study provides a molecular mechanism for pro-atherogenic effects of ANRIL at Chr9p21 and suggests a novel role for Alu elements in epigenetic gene regulation by long ncRNAs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cardiovascular magnetic resonance (CMR) has significantly revolutionized the comprehension and diagnosis of cardiac diseases, particularly through the utilization of late gadolinium enhancement (LGE) ...imaging for tissue characterization. LGE enables the visualization of expanded extracellular spaces in conditions such as fibrosis, fibrofatty tissue, or edema. The growing recognition of LGE's prognostic capacity underscores its importance, evident in the increasing explicit recommendations within guidelines. Notably, the contemporary characterization of cardiomyopathies relies on LGE-based scar assessment by CMR to a large extent. This review describes the pattern and prognostic value of LGE in detail for various cardiac diseases. Despite its merits, establishing LGE as a reliable risk marker encounters challenges. Limitations arise from the fact that not all diseases show LGE, and it should always be analyzed in the context of all CMR sequences and the patient's medical history. In summary, LGE stands as a robust indicator of adverse outcomes in diverse cardiovascular diseases. Its further integration into routine practice is desirable, necessitating widespread availability and application to accumulate both individual and scientific experience.
Noncommunicable diseases (NCDs) have become the primary health concern for most countries around the world. Currently, more than 36 million people worldwide die from NCDs each year, accounting for ...63% of annual global deaths; most are preventable. The global financial burden of NCDs is staggering, with an estimated 2010 global cost of $6.3 trillion (US dollars) that is projected to increase to $13 trillion by 2030. A number of NCDs share one or more common predisposing risk factors, all related to lifestyle to some degree: (1) cigarette smoking, (2) hypertension, (3) hyperglycemia, (4) dyslipidemia, (5) obesity, (6) physical inactivity, and (7) poor nutrition. In large part, prevention, control, or even reversal of the aforementioned modifiable risk factors are realized through leading a healthy lifestyle (HL). The challenge is how to initiate the global change, not toward increasing documentation of the scope of the problem but toward true action-creating, implementing, and sustaining HL initiatives that will result in positive, measurable changes in the previously defined poor health metrics. To achieve this task, a paradigm shift in how we approach NCD prevention and treatment is required. The goal of this American Heart Association/European Society of Cardiology/European Association for Cardiovascular Prevention and Rehabilitation/American College of Preventive Medicine policy statement is to define key stakeholders and highlight their connectivity with respect to HL initiatives. This policy encourages integrated action by all stakeholders to create the needed paradigm shift and achieve broad adoption of HL behaviors on a global scale.
A reduction in number and function of endothelial progenitor cells (EPCs) occurs in both physiologic aging and chronic heart failure (CHF). We assessed whether disease and aging have additive effects ...on EPCs or whether beneficial effects of exercise training are diminished in old age.
We randomized 60 patients with stable CHF and 60 referent controls to a training or a control group. To detect possible aging effects we included subjects below 55 (young) and above 65 years (older). Subjects in the training group exercised four times daily at 60% to 70% of VO2max for four weeks under supervision. At baseline and after the intervention the number and function of EPCs were assessed.
As compared with young referent controls, older referent controls showed at baseline a reduced EPC number (young: 190 ± 37 CD34/KDR positive cells/ml blood; older: 131 ± 26 CD34/KDR positive cells/ml blood; p < 0.05) and function (young: 230 ± 41 migrated cells/1000 plated cells; older: 185 ± 28 cells/1000 plated cells; p < 0.05). In young and older CHF patients EPC-number (young: 85 ± 21 CD34/KDR positive cells/ml blood; older: 78 ± 20 CD34/KDR positive cells/ml blood) and EPC-function (young: 113 ± 26 cells/1000 plated cells; older: 120 ± 27 cells/1000 plated cells) were impaired. As a result of exercise training, EPC function improved by 24% in older referent controls (p < 0.05), while it remained unchanged in young training referent controls and controls respectively. In young and older patients with CHF four weeks of exercise training resulted in a significant improvement in EPC numbers and EPC function (young: number +66% function +43%; p < 0.05; older: number +69% function +36%; p < 0.05). These results were accompanied by a significant increase in flow mediated dilatation in the training groups of young/older CHF patients and in older referent controls.
Four weeks of exercise training are effective in improving EPC number and EPC function in CHF patients. These training effects were not impaired among older patients, emphasizing the potentials of rehabilitation interventions in a patient group where CHF has a high prevalence.
Noncommunicable diseases (NCDs) have become the primary health concern for most countries around the world. Currently, more than 36 million people worldwide die from NCDs each year, accounting for ...63% of annual global deaths; most are preventable. The global financial burden of NCDs is staggering, with an estimated 2010 global cost of $6.3 trillion (US dollars) that is projected to increase to $13 trillion by 2030. A number of NCDs share one or more common predisposing risk factors, all related to lifestyle to some degree: (1) cigarette smoking, (2) hypertension, (3) hyperglycemia, (4) dyslipidemia, (5) obesity, (6) physical inactivity, and (7) poor nutrition. In large part, prevention, control, or even reversal of the aforementioned modifiable risk factors are realized through leading a healthy lifestyle (HL). The challenge is how to initiate the global change, not toward increasing documentation of the scope of the problem but toward true action-creating, implementing, and sustaining HL initiatives that will result in positive, measurable changes in the previously defined poor health metrics. To achieve this task, a paradigm shift in how we approach NCD prevention and treatment is required. The goal of this American Heart Association/European Society of Cardiology/European Association for Cardiovascular Prevention and Rehabilitation/American College of Preventive Medicine policy statement is to define key stakeholders and highlight their connectivity with respect to HL initiatives. This policy encourages integrated action by all stakeholders to create the needed paradigm shift and achieve broad adoption of HL behaviors on a global scale.
In the arterial wall nitric oxide (NO) is the key transmitter for endothelium-dependent regulation of vascular tone. It is produced in intact endothelial cells by endothelial NO synthase (eNOS) as ...the key enzyme from L-arginine. Endothelial NO generation is highly regulated by mechanical, humoral, and metabolic factors. The regulation of NO synthesis occurs at different levels: ENOS gene polymorphisms are related to eNOS expression and activity and may potentially increase coronary event rate, mRNA expression is influenced by estrogen status and shear stress, mRNA stability is enhanced by vascular endothelial growth factor (VEGF), and final enzyme activity is regulated by the phosphorylation status at serine/threonine residues. Released from endothelial cells NO is rapidly transported to the neighboring vascular smooth muscle cells (VSMCs), where it induces the production of cGMP as a second messenger. CGMP in turn increases Ca2+ uptake into intracellular calcium stores thereby lowering Ca2+i and inducing VSMC relaxation and vasodilation. On its way to the VSMCs NO may be prematurely degraded by reactive oxygen species. On the other hand, chronic endurance exercise with regular bouts of increased laminar flow along the endothelium has the potential to increase eNOS mRNA expression and phosphorylation via AKT (protein kinase B) and to reduce oxidative stress by improving antioxidative protection. The growing knowledge about the complex regulation of NO synthesis and degradation in cardiovascular diseases and its response to exercise has led to a new understanding of the protective effects of long-term habitual physical activity against atherosclerotic heart disease and vascular aging.
Inflammatory cytokines like tumor necrosis factor alpha (TNF-α) are elevated in congestive heart failure and are known to induce the production of reactive oxygen species as well as to deteriorate ...respiratory muscle function.
Given the antioxidative effects of exercise training, the aim of the present study was to investigate if exercise training is capable of preventing a TNF-α induced loss of diaphragmatic force in mice and, if so, to elucidate the potential underlying mechanisms.
Prior to intraperitoneal injection of TNF-α or saline, C57Bl6 mice were assigned to four weeks of exercise training or sedentary behavior. Diaphragmatic force and power generation were determined in vitro. Expression/activity of radical scavenger enzymes, enzymes producing reactive oxygen species and marker of oxidative stress were measured in the diaphragm.
In sedentary animals, TNF-α reduced specific force development by 42% concomitant with a 2.6-fold increase in the amount of carbonylated α-actin and creatine kinase. Furthermore, TNF-α led to an increased NAD(P)H oxidase activity in both sedentary and exercised mice whereas xanthine oxidase activity and intramitochondrial ROS production was only enhanced in sedentary animals by TNF-α. Exercise training prevented the TNF-α induced force reduction and led to an enhanced mRNA expression and activity of glutathione peroxidase. Carbonylation of proteins, in particular of α-actin and creatine kinase, was diminished by exercise training.
TNF-α reduces the force development in the diaphragm of mice. This effect is almost abolished by exercise training. This may be a result of reduced carbonylation of proteins due to the antioxidative properties of exercise training.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK