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BACKGROUND: Embolism from unstable atheromas in the carotid bifurcation is a major cause of stroke. Here, we analysed gene expression in endarterectomies from patients with symptomatic (S) and asymptomatic (AS) carotid stenosis to identify pathways linked to plaque instability. METHODS: Microarrays were prepared from plaques (n = 127) and peripheral blood samples (n = 96) of S and AS patients. Gene set enrichment, pathway mapping and network analyses of differentially expressed genes were performed. RESULTS: These studies revealed upregulation of haemoglobin metabolism (P = 2.20E-05) and bone resorption (P = 9.63E-04) in S patients. Analysis of subgroups of patients indicated enrichment of calcification and osteoblast differentiation in S patients on statins, as well as inflammation and apoptosis in plaques removed >1 month compared to <2 weeks after symptom. By prediction profiling, a panel of 30 genes, mostly transcription factors, discriminated between plaques from S versus AS patients with 78% accuracy. By meta-analysis, common gene networks associated with atherosclerosis mapped to hypoxia, chemokines, calcification, actin cytoskeleton and extracellular matrix. A set of dysregulated genes (LMOD1, SYNPO2, PLIN2 and PPBP) previously not described in atherosclerosis were identified from microarrays and validated by quantitative PCR and immunohistochemistry. CONCLUSIONS: Our findings confirmed a central role for inflammation and proteases in plaque instability, and highlighted haemoglobin metabolism and bone resorption as important pathways. Subgroup analysis suggested prolonged inflammation following the symptoms of plaque instability and calcification as a possible stabilizing mechanism by statins. In addition, transcriptional regulation may play an important role in the determination of plaque phenotype. The results from this study will serve as a basis for further exploration of molecular signatures in carotid atherosclerosis.
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Enfermedades de las Arterias Carótidas/genética , Transcriptoma , Anciano , Femenino , Redes Reguladoras de Genes , Humanos , Masculino , Transducción de SeñalRESUMEN
TCF21 is a basic helix-loop-helix transcription factor that has recently been implicated as contributing to susceptibility to coronary heart disease based on genome wide association studies. In order to identify transcriptionally regulated target genes in a major disease relevant cell type, we performed siRNA knockdown of TCF21 in in vitro cultured human coronary artery smooth muscle cells and compared the transcriptome of siTCF21 versus siCONTROL treated cells. The raw (FASTQ) as well as processed (BED) data from 3 technical replicates per treatment has been deposited with Gene Expression Omnibus (GSE44461).
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Cardiovascular disease remains the most prevalent cause of human morbidity and mortality in ageing Western societies. Basic and translational scientific efforts have focused on the development and improvement of diagnostic and therapeutic strategies to limit the burden of associated diseases, such as stroke and myocardial infarction, and diabetes mellitus and arterial hypertension. Progress in molecular medicine and biology has unravelled a complex epigenetic and post-transcriptional gene-regulating machinery in humans which may limit disease development. An increasing number of attractive molecular strategies, which use the potential of modulating noncoding RNAs, have surfaced over the last decade. Currently, the most extensively studied gene-regulating RNA subspecies are microRNAs, which have been shown to adjust the translational output of coding transcripts by enforcing their degradation and inhibiting their translation into protein. Key findings indicate that microRNAs act as crucial regulators in the majority of human pathologies. Thus, recent research has focused on detecting and modulating microRNAs for therapeutic and biomarker purposes. This review focuses on main and repeated discoveries regarding the role and the therapeutic and biomarker feasibility of microRNAs during cardiovascular disease development and exacerbation.
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Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/terapia , Terapia Genética , MicroARNs/fisiología , Animales , Biomarcadores/sangre , Enfermedades Cardiovasculares/diagnóstico , Humanos , MicroARNs/antagonistas & inhibidores , MicroARNs/sangre , Factores de RiesgoRESUMEN
A 27-year old pregnant woman presented in our emergency department with syncope, dyspnea and complaints about an overall impairment. She had received aortic alloplastic heart valve replacement due to a congenital, valvular stenosis in 1993. We diagnosed a prosthetic heart valve thrombosis associated with cardiac decompensation. Due to tachycardia and critical hypotension we decided to perform fibrinolytic therapy with tenecteplase. After fibrinolysis both prosthetic heart valve leaflets were separating in normal and regular function. The patient was initially anticoagulated with low molecular weight heparin, which was switched during the hospital stay to unfractionated heparin. Later oral anticoagulation with phenprocoumon was initiated. At 36 weeks of gestation an uneventful elective abdominal caesarean section was performed. The mother and the newborn were in healthy condition. Hypercoaguability in pregnancy is a serious problem, especially for patients who already have an existing indication for therapeutic anticoagulation. Fibrinolysis should definitely be considered an option during pregnancy in critical and life-threatening situations.