Subclinical atherosclerosis and accelerated epigenetic age mediated by inflammation: a multi-omics study.

AIMS: Epigenetic age is emerging as a personalized and accurate predictor of biological age. The aim of this article is to assess the association of subclinical atherosclerosis with accelerated epigenetic age and to investigate the underlying mechanisms mediating this association. METHODS AND RESULTS: Whole blood methylomics, transcriptomics, and plasma proteomics were obtained for 391 participants of the Progression of Early Subclinical Atherosclerosis study. Epigenetic age was calculated from methylomics data for each participant. Its divergence from chronological age is termed epigenetic age acceleration. Subclinical atherosclerosis burden was estimated by multi-territory 2D/3D vascular ultrasound and by coronary artery calcification. In healthy individuals, the presence, extension, and progression of subclinical atherosclerosis were associated with a significant acceleration of the Grim epigenetic age, a predictor of health and lifespan, regardless of traditional cardiovascular risk factors. Individuals with an accelerated Grim epigenetic age were characterized by an increased systemic inflammation and associated with a score of low-grade, chronic inflammation. Mediation analysis using transcriptomics and proteomics data revealed key pro-inflammatory pathways (IL6, Inflammasome, and IL10) and genes (IL1B, OSM, TLR5, and CD14) mediating the association between subclinical atherosclerosis and epigenetic age acceleration. CONCLUSION: The presence, extension, and progression of subclinical atherosclerosis in middle-aged asymptomatic individuals are associated with an acceleration in the Grim epigenetic age. Mediation analysis using transcriptomics and proteomics data suggests a key role of systemic inflammation in this association, reinforcing the relevance of interventions on inflammation to prevent cardiovascular disease.

Intrapericardial Administration of Secretomes from Menstrual Blood-Derived Mesenchymal Stromal Cells: Effects on Immune-Related Genes in a Porcine Model of Myocardial Infarction.

Acute myocardial infarction (AMI) is a manifestation of ischemic heart disease where the immune system plays an important role in the re-establishment of homeostasis. We hypothesize that the anti-inflammatory activity of secretomes from menstrual blood-derived mesenchymal stromal cells (S-MenSCs) and IFNγ/TNFα-primed MenSCs (S-MenSCs*) may be considered a therapeutic option for the treatment of AMI. To assess this hypothesis, we have evaluated the effect of S-MenSCs and S-MenSCs* on cardiac function parameters and the involvement of immune-related genes using a porcine model of AMI. Twelve pigs were randomly divided into three biogroups: AMI/Placebo, AMI/S-MenSCs, and AMI/S-MenSCs*. AMI models were generated using a closed chest coronary occlusion-reperfusion procedure and, after 72 h, the different treatments were intrapericardially administered. Cardiac function parameters were monitored by magnetic resonance imaging before and 7 days post-therapy. Transcriptomic analyses in the infarcted tissue identified 571 transcripts associated with the Gene Ontology term Immune response, of which 57 were differentially expressed when different biogroups were compared. Moreover, a prediction of the interactions between differentially expressed genes (DEGs) and miRNAs from secretomes revealed that some DEGs in the infarction area, such as STAT3, IGFR1, or BCL6 could be targeted by previously identified miRNAs in secretomes from MenSCs. In conclusion, the intrapericardial administration of secretome early after infarction has a significant impact on the expression of immune-related genes in the infarcted myocardium. This confirms the immunomodulatory potential of intrapericardially delivered secretomes and opens new therapeutic perspectives in myocardial infarction treatment.

The Clinical outcomes, healthcare resource utilization, and related costs (COHERENT) model. Application in heart failure patients.

INTRODUCTION AND OBJECTIVES: Composite endpoints are widely used but have several limitations. The Clinical outcomes, healthcare resource utilization and related costs (COHERENT) model is a new approach for visually displaying and comparing composite endpoints including all their components (incidence, timing, duration) and related costs. We aimed to assess the validity of the COHERENT model in a patient cohort. METHODS: A color graphic system displaying the percentage of patients in each clinical situation (vital status and location: at home, emergency department [ED] or hospital) and related costs at each time point during follow-up was created based on a list of mutually exclusive clinical situations coded in a hierarchical fashion. The system was tested in a cohort of 1126 patients with acute heart failure from 25 hospitals. The system calculated and displayed the time spent in each clinical situation and health care resource utilization-related costs over 30 days. RESULTS: The model illustrated the times spent over 30 days (2.12% in ED, 23.6% in index hospitalization, 2.7% in readmissions, 65.5% alive at home, and 6.02% dead), showing significant differences between patient groups, hospitals, and health care systems. The tool calculated and displayed the daily and cumulative health care-related costs over time (total, €4 895 070; mean, €144.91 per patient/d). CONCLUSIONS: The COHERENT model is a new, easy-to-interpret, visual display of composite endpoints, enabling comparisons between patient groups and cohorts, including related costs. The model may constitute a useful new approach for clinical trials or observational studies, and a tool for benchmarking, and value-based health care implementation.

Aging-Associated miR-217 Aggravates Atherosclerosis and Promotes Cardiovascular Dysfunction.

OBJECTIVE: microRNAs are master regulators of gene expression with essential roles in virtually all biological processes. miR-217 has been associated with aging and cellular senescence, but its role in vascular disease is not understood. Approach and Results: We have used an inducible endothelium-specific knock-in mouse model to address the role of miR-217 in vascular function and atherosclerosis. miR-217 reduced NO production and promoted endothelial dysfunction, increased blood pressure, and exacerbated atherosclerosis in proatherogenic apoE-/- mice. Moreover, increased endothelial miR-217 expression led to the development of coronary artery disease and altered left ventricular heart function, inducing diastolic and systolic dysfunction. Conversely, inhibition of endogenous vascular miR-217 in apoE-/- mice improved vascular contractility and diminished atherosclerosis. Transcriptome analysis revealed that miR-217 regulates an endothelial signaling hub and downregulates a network of eNOS (endothelial NO synthase) activators, including VEGF (vascular endothelial growth factor) and apelin receptor pathways, resulting in diminished eNOS expression. Further analysis revealed that human plasma miR-217 is a biomarker of vascular aging and cardiovascular risk. CONCLUSIONS: Our results highlight the therapeutic potential of miR-217 inhibitors in aging-related cardiovascular disease.

Unraveling the Molecular Signature of Extracellular Vesicles From Endometrial-Derived Mesenchymal Stem Cells: Potential Modulatory Effects and Therapeutic Applications.

Endometrial-derived Mesenchymal Stem Cells (endMSCs) are involved in the regeneration and remodeling of human endometrium, being considered one of the most promising candidates for stem cell-based therapies. Their therapeutic effects have been found to be mediated by extracellular vesicles (EV-endMSCs) with pro-angiogenic, anti-apoptotic, and immunomodulatory effects. Based on that, the main goal of this study was to characterize the proteome and microRNAome of these EV-endMSCs by proteomics and transcriptomics approaches. Additionally, we hypothesized that inflammatory priming of endMSCs may contribute to modify the therapeutic potential of these vesicles. High-throughput proteomics revealed that 617 proteins were functionally annotated as Extracellular exosome (GO:0070062), corresponding to the 70% of the EV-endMSC proteome. Bioinformatics analyses allowed us to identify that these proteins were involved in adaptive/innate immune response, complement activation, antigen processing/presentation, negative regulation of apoptosis, and different signaling pathways, among others. Of note, multiplexed quantitative proteomics and Systems Biology analyses showed that IFNγ priming significantly modulated the protein profile of these vesicles. As expected, proteins involved in antigen processing and presentation were significantly increased. Interestingly, immunomodulatory proteins, such as CSF1, ERAP1, or PYCARD were modified. Regarding miRNAs expression profile in EV-endMSCs, Next-Generation Sequencing (NGS) showed that the preferred site of microRNAome targeting was the nucleus (n = 371 microTargets), significantly affecting signal transduction (GO:0007165), cell proliferation (GO:0008283), and apoptotic processes (GO:0006915), among others. Interestingly, NGS analyses highlighted that several miRNAs, such as hsa-miR-150-5p or hsa-miR-196b-5p, were differentially expressed in IFNγ-primed EV-endMSCs. These miRNAs have a functional involvement in glucocorticoid receptor signaling, IL-6/8/12 signaling, and in the role of macrophages. In summary, these results allowed us to understand the complexity of the molecular networks in EV-endMSCs and their potential effects on target cells. To our knowledge, this is the first comprehensive study based on proteomic and genomic approaches to unravel the therapeutic potential of these extracellular vesicles, that may be used as immunomodulatory effectors in the treatment of inflammatory conditions.

The human HDL proteome displays high inter-individual variability and is altered dynamically in response to angioplasty-induced atheroma plaque rupture.

Recent findings support potential roles for HDL in cardiovascular pathophysiology not related to lipid metabolism. We address whether HDL proteome is dynamically altered in atheroma plaque rupture. We used immunoaffinity purification of HDL samples from coronary artery disease patients before and after percutaneous transluminal coronary angioplasty (PTCA), a model of atheroma plaque disruption. Samples were analyzed by quantitative proteomics using stable isotope labeling and results were subjected to statistical analysis of protein variance using a novel algorithm. We observed high protein variability in HDL composition between individuals, indicating that HDL protein composition is highly patient-specific. However, intra-individual protein variances remained at low levels, confirming the reproducibility of the method used for HDL isolation and protein quantification. A systems biology analysis of HDL protein alterations induced by PTCA revealed an increase in two protein clusters that included several apolipoproteins, fibrinogen-like protein 1 and other intracellular proteins, and a decrease in antithrombin-III, annexin A1 and several immunoglobulins. Our results support the concept of HDL as dynamic platforms that donate and receive a variety of molecules and provide an improved methodology to use HDL proteome for the systematic analysis of differences among individuals and the search for cardiovascular biomarkers. Biological significance The HDL proteome is an interesting model of clinical relevance and has been previously described to be dynamically altered in response to pathophysiological conditions and cardiovascular diseases. Our study suggests that interindividual variability of HDL proteome is higher than previously thought and provided the detection of a set of proteins that changed their abundance in response to plaque rupture, supporting the concept of HDL as dynamic platforms that donate and receive a variety of molecules.