Cardiovascular disease (CVD) is the most common cause of death in industrialized countries. One underlying cause is atherosclerosis, which is a systemic disease characterized by plaques of retained ...lipids, inflammatory cells, apoptotic cells, calcium and extracellular matrix (ECM) proteins in the arterial wall. The biologic composition of an atherosclerotic plaque determines whether the plaque is more or less vulnerable, that is prone to rupture or erosion. Here, the ECM and tissue repair play an important role in plaque stability, vulnerability and progression. This review will focus on ECM remodelling in atherosclerotic plaques, with focus on how ECM biomarkers might predict plaque vulnerability and outcome.
There is a need for precision medicine and an unspoken promise of an optimal approach for identification of the right patients for value-based medicine based on big data. However, there may be a ...misconception that measurement of proteins is more valuable than measurement of fewer selected biomarkers. In population-based research, variation may be somewhat eliminated by quantity. However, this fascination of numbers may limit the attention to and understanding of the single. This review highlights that protein measurements (with collagens as examples) may mean different things depending on the targeted epitope – formation or degradation of tissues, and even signaling potential of proteins.
PubMed was searched for collagen, neo-epitope, biomarkers. Results: Ample examples of assays with specific epitopes, either pathological such as HbA1c, or domain specific such as pro-peptides, which total protein arrays would not have identified were evident.
We suggest that big data may be considered as the funnel of data points, in which most important parameters will be selected. If the technical precision is low or the biological accuracy is limited, and we include suboptimal quality of biomarkers, disguised as big data, we may not be able to fulfill the promise of helping patients searching for the optimal treatment. Alternatively, if the technical precision of the total protein quantification is high, but we miss the functional domains with the most considerable biological meaning, we miss the most important and valuable information of a given protein. This review highlights that measurements of the same protein in different ways may provide completely different meanings. We need to understand the pathological importance of each epitope quantified to maximize protein measurements.
Abstract
Background/Aim
Accumulation of extracellular matrix (ECM) proteins is the hallmark of cardiac fibrosis, causing stiffening of the ventricular wall, which can lead to heart failure and ...ultimately death. Many different cell types and growth factors are involved in this process but fibroblasts are the main source of ECM proteins. Here we present results from an in vitro model indicating that endotrophin (ETP), a collagen type VI fragment, activates cardiac fibroblasts and induces fibrogenesis.
Methods
The effect of ETP, transforming growth factor (TGF)-β and platelet-derived growth factor (PDGF)-DD on ECM protein synthesis was assessed in a scar-in-a-jar (SiaJ) cell model using human cardiac fibroblasts isolated from the atrium of an adult healthy donor. Cells were seeded in 48-well plates at a density of 30.000 cells/well and incubated for 24H in Dulbecco's Modified Eagle's medium (DMEM) + 10% fetal bovine serum (FBS). Serum starvation was done by seeding the cells for further 24H in DMEM + 0.4% FBS. Fresh medium was added at day 0 with 37.5/25mg/mL Ficoll 70/400 and 1% ascorbic acid, containing 11.75 nM human recombinant ETP, 0.04 nM TGF-β, 0.39 nM PDGF-DD or a vehicle control. Medium was changed and collected at day 3 and 6. Biomarkers of type I (PRO-C1), III (PRO-C3), VI (PRO-C6) collagens and fibronectin (FBN-C) formation were assessed in the medium by ELISAs developed at Nordic Bioscience.
Results
ETP induced a significant increase in PRO-C1, PRO-C3 and FBN-C (comparable to TGF-β and PDGF-DD) within the first three days of the experiment, compared to the vehicle control. The levels remained significantly increased for PRO-C3 and FBN-C throughout the experiment, and non-significantly elevated for PRO-C1, compared to the vehicle control. PDGF-DD significantly induced synthesis of type VI collagen compared to the vehicle control, while TGF-β induced a small increase in synthesis from day 0–3, after which it seemed to inhibit synthesis.
Conclusion
For the first time, a direct pro-fibrotic effect on fibroblasts induced by ETP has been shown. This novel pathway of activation could play an important role in regulating cardiac fibrosis, and thus prove to be a therapeutic target. This SiaJ model in combination with the investigated biomarkers of ECM formation could be used to further elucidate the mechanisms behind cardiac fibrosis.
Psychiatric disorders are characterized by major fluctuations in psychological function over the course of weeks and months, but the dynamic characteristics of brain function over this timescale in ...healthy individuals are unknown. Here, as a proof of concept to address this question, we present the MyConnectome project. An intensive phenome-wide assessment of a single human was performed over a period of 18 months, including functional and structural brain connectivity using magnetic resonance imaging, psychological function and physical health, gene expression and metabolomics. A reproducible analysis workflow is provided, along with open access to the data and an online browser for results. We demonstrate dynamic changes in brain connectivity over the timescales of days to months, and relations between brain connectivity, gene expression and metabolites. This resource can serve as a testbed to study the joint dynamics of human brain and metabolic function over time, an approach that is critical for the development of precision medicine strategies for brain disorders.
Aims
Extracellular matrix remodelling is one of the key pathways involved in heart failure (HF) progression. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) may have a role in attenuating ...myocardial fibrosis. The impact of SGLT2i on blood markers of collagen turnover in humans is not fully elucidated. This study aimed to investigate the effect of empagliflozin on serum markers of collagen turnover in patients enrolled in the EMPEROR‐Preserved and EMPEROR‐Reduced trials.
Methods and results
Overall, 1084 patients (545 in empagliflozin and 539 in placebo) were included in the analysis. Procollagen type I carboxy‐terminal propeptide (PICP), a fragment of N‐terminal type III collagen (PRO‐C3), procollagen type I amino‐terminal peptide (PINP), a fragment of C‐terminal type VIa3 collagen (PRO‐C6), a fragment of type I collagen (C1M), and a fragment of type III collagen (C3M) were measured in serum at baseline, 12 and 52 weeks. A mixed model repeated measurements model was used to evaluate the effect of empagliflozin versus placebo on the analysed biomarkers. Higher baseline PICP, PRO‐C6 and PINP levels were associated with older age, a more severe HF presentation, higher levels of natriuretic peptides and high‐sensitivity troponin T, and the presence of comorbid conditions such as chronic kidney disease and atrial fibrillation. Higher PICP levels were associated with the occurrence of the study primary endpoint (a composite of HF hospitalization or cardiovascular death), and PRO‐C6 and PINP were associated with the occurrence of sustained worsening of kidney function. On the other hand, PRO‐C3, C1M, and C3M were not associated with worse HF severity or study outcomes. Compared to placebo, empagliflozin reduced PICP at week 12 by 5% and at week 52 by 8% (week 12: geometric mean ratio = 0.95, 95% confidence interval CI 0.91–0.99, p = 0.012; week 52: geometric mean ratio = 0.92, 95% CI 0.88–0.97, p = 0.003).
Additionally, empagliflozin reduced PRO‐C3 at week 52 by 7% (week 12: geometric mean ratio = 0.98, 95% CI 0.95–1.02, p = 0.42; week 52: geometric mean ratio = 0.93, 95% CI 0.89–0.98, p = 0.003), without impact on other collagen markers.
Conclusion
Our observations are consistent with experimental observations that empagliflozin down‐regulates profibrotic signalling. The importance of such an effect for the clinical benefits of SGLT2i in HF remains to be elucidated.
•Atrial fibrillation and composition and remodeling of the cardiac tissue.•Pro-fibrotic molecules regulating cardiac fibrosis.•Traditional and collagen biomarkers of atrial fibrillation, and how the ...protein fingerprint technology can be implicated.•Perspectives on the clinical utility of biomarkers of atrial fibrillation.
The involvement of fibrosis as an underlying pathology in heart diseases is becoming increasingly clear. In recent years, fibrosis has been granted a causative role in heart diseases and is now emerging as a major contributor to Atrial Fibrillation (AF) pathogenesis. AF is the most common arrhythmia encountered in the clinic, but the substrate for AF is still being debated. Consensus in the field is a combination of cardiac tissue remodeling, inflammation and genetic predisposition. The extracellular matrix (ECM) is subject of growing investigation, since measuring circulatory biomarkers of ECM formation and degradation provides both diagnostic and prognostic information. However, fibrosis is not just fibrosis. Each specific collagen biomarker holds information on regulatory mechanisms, as well as information about which section of the ECM is being remodeled, providing a detailed description of cardiac tissue homeostasis. This review entails an overview of the implication of fibrosis in AF, the different collagens and their significance, and the potential of using biomarkers of ECM remodeling as tools for understanding AF pathogenesis and identifying patients at risk for further disease progression.
The total molecular mass of individual postsynaptic densities (PSDs) isolated from rat forebrain was measured by scanning transmission EM. PSDs had a mean diameter of 360 nm and molecular mass of ...1.10 ± 0.36 GDa. Because the mass represents the sum of the molecular masses of all of the molecules comprising a PSD, it becomes possible to derive the number of copies of each protein, once its relative mass contribution is known. Mass contributions of PSD-95, synapse-associated protein (SAP)97, and α - Ca2+/calmodulin-dependent protein kinase II (CaMKII) were determined by quantitative gel electrophoresis of PSD fractions. The number of PSD-95 molecules per average PSD, contributing 2.3% of the mass of the PSD, was calculated to be 300, whereas the number of SAP97 molecules, contributing 0.9% of the mass of the PSD, was 90. The α-CaMKII holoenzymes, which contribute 6% of the mass when brains are homogenized within 2 min of interrupting blood flow, have 80 holoenzymes associated with a typical PSD. When blood flow is interrupted 15 min before homogenization, the average mass of PSDs increases by ≈40%. The additional α-CaMKII associated with PSDs accounts for up to 20% of this mass increase, representing the addition of 100-200 α-CaMKII holoenzymes.
Earth-abundant copper-barium-thiostannate Cu2BaSnS4 (CBTS)-based thin films have recently been reported to exhibit the optoelectronic and defect properties suitable as absorbers for ...photoelectrochemical (PEC) water splitting and the top cell of tandem photovoltaic solar cells. However, the photocurrents of CBTS-based PEC devices are still much lower than the theoretical value, partially due to ineffective charge collection at CBTS/water interface and instability of CBTS in electrolytes. Here, we report on overcoming these issues by employing overlayer engineering. We find that CdS/ZnO/TiO2 overlayers can significant-ly improve the PEC performance, achieving saturated cathodic photocurrents up to 7.8 mA cm-2 at the potential of -0.10 V versus reversible hydrogen electrode (RHE) in a neutral electrolyte solution, which is much higher than the best bare CBTS film attaining a photocurrent of 4.8 mA cm-2 at the potential of -0.2 V versus RHE. Finally, our results suggest a viable approach for improving the performance of CBTS-based PEC cells.
•The PRO-C28 assay was technically robust and have high specificity for the target epitope.•PRO-C28 levels are significantly elevated in blood-based samples from HFpEF and cancer patients.•PRO-C28 ...discriminated between healthy controls and patients with high statistical power.
Increased turnover of extracellular matrix proteins is seen in many different diseases and is an underlying and driving feature of pathogenesis. An increased ratio of formation over degradation of extracellular matrix proteins, such as collagens, leads to accumulation of proteins in the tissues, ultimately impairing organ function. Understanding how this balance is regulated is key to providing deeper insight into high extracellular matrix turnover diseases. Type XXVIII collagen is a novel collagen with limited information available in relation to expression, tissue prevalence and clinical implication. We generated a novel, technically robust ELISA to measure a C-terminal fragment of type XXVIII collagen in plasma and serum (PRO-C28). PRO-C28 was found to be significantly elevated in circulation in patients with heart failure with preserved ejection fraction (HFpEF) and in patients with lung cancer. Additionally, PRO-C28 correlated significantly to NT-proBNP levels in HFpEF patients. PRO-C28 levels were elevated in diseases characterized by high ECM-turnover. This suggests that type XXVIII collagen may play a role in fibroproliferative disorders in the heart and the lungs.
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