Publications by authors named "Manuel Mayr"

247 Publications

DRP1-a Novel Regulator of PCSK9 Secretion and Degradation.

Cardiovasc Res 2021 Jul 15. Epub 2021 Jul 15.

King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, United Kingdom.

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http://dx.doi.org/10.1093/cvr/cvab227DOI Listing
July 2021

Lessons from the spatiotemporal expression patterns of RNA vs. proteins during the cell cycle.

Cardiovasc Res 2021 Jul;117(8):e91-e93

King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, Strand, London WC2R 2LS, UK.

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http://dx.doi.org/10.1093/cvr/cvab196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262630PMC
July 2021

SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care.

Nat Commun 2021 06 7;12(1):3406. Epub 2021 Jun 7.

Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King's College London, London, UK.

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.
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http://dx.doi.org/10.1038/s41467-021-23494-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184784PMC
June 2021

Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation.

EMBO Mol Med 2021 Jun 16;13(6):e13074. Epub 2021 May 16.

Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

The phospholamban (PLN) p.Arg14del mutation causes dilated cardiomyopathy, with the molecular disease mechanisms incompletely understood. Patient dermal fibroblasts were reprogrammed to hiPSC, isogenic controls were established by CRISPR/Cas9, and cardiomyocytes were differentiated. Mutant cardiomyocytes revealed significantly prolonged Ca transient decay time, Ca -load dependent irregular beating pattern, and lower force. Proteomic analysis revealed less endoplasmic reticulum (ER) and ribosomal and mitochondrial proteins. Electron microscopy showed dilation of the ER and large lipid droplets in close association with mitochondria. Follow-up experiments confirmed impairment of the ER/mitochondria compartment. PLN p.Arg14del end-stage heart failure samples revealed perinuclear aggregates positive for ER marker proteins and oxidative stress in comparison with ischemic heart failure and non-failing donor heart samples. Transduction of PLN p.Arg14del EHTs with the Ca -binding proteins GCaMP6f or parvalbumin improved the disease phenotype. This study identified impairment of the ER/mitochondria compartment without SR dysfunction as a novel disease mechanism underlying PLN p.Arg14del cardiomyopathy. The pathology was improved by Ca -scavenging, suggesting impaired local Ca cycling as an important disease culprit.
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http://dx.doi.org/10.15252/emmm.202013074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185541PMC
June 2021

Fibroblast GATA-4 and GATA-6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis.

Basic Res Cardiol 2021 04 19;116(1):26. Epub 2021 Apr 19.

Department of Cardiology and Angiology, Hannover Medical School, 30625, Hannover, Germany.

Heart failure due to high blood pressure or ischemic injury remains a major problem for millions of patients worldwide. Despite enormous advances in deciphering the molecular mechanisms underlying heart failure progression, the cell-type specific adaptations and especially intercellular signaling remain poorly understood. Cardiac fibroblasts express high levels of cardiogenic transcription factors such as GATA-4 and GATA-6, but their role in fibroblasts during stress is not known. Here, we show that fibroblast GATA-4 and GATA-6 promote adaptive remodeling in pressure overload induced cardiac hypertrophy. Using a mouse model with specific single or double deletion of Gata4 and Gata6 in stress activated fibroblasts, we found a reduced myocardial capillarization in mice with Gata4/6 double deletion following pressure overload, while single deletion of Gata4 or Gata6 had no effect. Importantly, we confirmed the reduced angiogenic response using an in vitro co-culture system with Gata4/6 deleted cardiac fibroblasts and endothelial cells. A comprehensive RNA-sequencing analysis revealed an upregulation of anti-angiogenic genes upon Gata4/6 deletion in fibroblasts, and siRNA mediated downregulation of these genes restored endothelial cell growth. In conclusion, we identified a novel role for the cardiogenic transcription factors GATA-4 and GATA-6 in heart fibroblasts, where both proteins act in concert to promote myocardial capillarization and heart function by directing intercellular crosstalk.
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http://dx.doi.org/10.1007/s00395-021-00862-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055639PMC
April 2021

Lipoprotein compartmentalisation as a regulator of PCSK9 activity.

J Mol Cell Cardiol 2021 Jun 20;155:21-24. Epub 2021 Feb 20.

King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, United Kingdom. Electronic address:

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http://dx.doi.org/10.1016/j.yjmcc.2021.02.004DOI Listing
June 2021

Loss of hepatic miR-33 improves metabolic homeostasis and liver function without altering body weight or atherosclerosis.

Proc Natl Acad Sci U S A 2021 02;118(5)

Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520;

miR-33 is an intronic microRNA within the gene encoding the SREBP2 transcription factor. Like its host gene, miR-33 has been shown to be an important regulator of lipid metabolism. Inhibition of miR-33 has been shown to promote cholesterol efflux in macrophages by targeting the cholesterol transporter ABCA1, thus reducing atherosclerotic plaque burden. Inhibition of miR-33 has also been shown to improve high-density lipoprotein (HDL) biogenesis in the liver and increase circulating HDL-C levels in both rodents and nonhuman primates. However, evaluating the extent to which these changes in HDL metabolism contribute to atherogenesis has been hindered by the obesity and metabolic dysfunction observed in whole-body miR-33-knockout mice. To determine the impact of hepatic miR-33 deficiency on obesity, metabolic function, and atherosclerosis, we have generated a conditional knockout mouse model that lacks miR-33 only in the liver. Characterization of this model demonstrates that loss of miR-33 in the liver does not lead to increased body weight or adiposity. Hepatic miR-33 deficiency actually improves regulation of glucose homeostasis and impedes the development of fibrosis and inflammation. We further demonstrate that hepatic miR-33 deficiency increases circulating HDL-C levels and reverse cholesterol transport capacity in mice fed a chow diet, but these changes are not sufficient to reduce atherosclerotic plaque size under hyperlipidemic conditions. By elucidating the role of miR-33 in the liver and the impact of hepatic miR-33 deficiency on obesity and atherosclerosis, this work will help inform ongoing efforts to develop novel targeted therapies against cardiometabolic diseases.
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http://dx.doi.org/10.1073/pnas.2006478118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865172PMC
February 2021

Systems biology in cardiovascular disease: a multiomics approach.

Nat Rev Cardiol 2021 May 18;18(5):313-330. Epub 2020 Dec 18.

King's British Heart Foundation Centre, King's College London, London, UK.

Omics techniques generate large, multidimensional data that are amenable to analysis by new informatics approaches alongside conventional statistical methods. Systems theories, including network analysis and machine learning, are well placed for analysing these data but must be applied with an understanding of the relevant biological and computational theories. Through applying these techniques to omics data, systems biology addresses the problems posed by the complex organization of biological processes. In this Review, we describe the techniques and sources of omics data, outline network theory, and highlight exemplars of novel approaches that combine gene regulatory and co-expression networks, proteomics, metabolomics, lipidomics and phenomics with informatics techniques to provide new insights into cardiovascular disease. The use of systems approaches will become necessary to integrate data from more than one omic technique. Although understanding the interactions between different omics data requires increasingly complex concepts and methods, we argue that hypothesis-driven investigations and independent validation must still accompany these novel systems biology approaches to realize their full potential.
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http://dx.doi.org/10.1038/s41569-020-00477-1DOI Listing
May 2021

A Proteomics-Based Assessment of Inflammation Signatures in Endotoxemia.

Mol Cell Proteomics 2021 Feb 24;20:100021. Epub 2021 Feb 24.

King's College London British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, London, United Kingdom. Electronic address:

We have previously shown that multimers of plasma pentraxin-3 (PTX3) were predictive of survival in patients with sepsis. To characterize the release kinetics and cellular source of plasma protein changes in sepsis, serial samples were obtained from healthy volunteers (n = 10; three time points) injected with low-dose endotoxin (lipopolysaccharide [LPS]) and analyzed using data-independent acquisition MS. The human plasma proteome response was compared with an LPS-induced endotoxemia model in mice. Proteomic analysis of human plasma revealed a rapid neutrophil degranulation signature, followed by a rise in acute phase proteins. Changes in circulating PTX3 correlated with increases in neutrophil-derived proteins following LPS injection. Time course analysis of the plasma proteome in mice showed a time-dependent increase in multimeric PTX3, alongside increases in neutrophil-derived myeloperoxidase (MPO) upon LPS treatment. The mechanisms of oxidation-induced multimerization of PTX3 were explored in two genetic mouse models: MPO global knock-out (KO) mice and LysM Cre Nox2 KO mice, in which NADPH oxidase 2 (Nox2) is only deficient in myeloid cells. Nox2 is the enzyme responsible for the oxidative burst in neutrophils. Increases in plasma multimeric PTX3 were not significantly different between wildtype and MPO or LysM Cre Nox2 KO mice. Thus, PTX3 may already be stored and released in a multimeric form. Through in vivo neutrophil depletion and multiplexed vascular proteomics, PTX3 multimer deposition within the aorta was confirmed to be neutrophil dependent. Proteomic analysis of aortas from LPS-injected mice returned PTX3 as the most upregulated protein, where multimeric PTX3 was deposited as early as 2 h post-LPS along with other neutrophil-derived proteins. In conclusion, the rise in multimeric PTX3 upon LPS injection correlates with neutrophil-related protein changes in plasma and aortas. MPO and myeloid Nox2 are not required for the multimerization of PTX3; instead, neutrophil extravasation is responsible for the LPS-induced deposition of multimeric PTX3 in the aorta.
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http://dx.doi.org/10.1074/mcp.RA120.002305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950208PMC
February 2021

Paracrine signalling by cardiac calcitonin controls atrial fibrogenesis and arrhythmia.

Nature 2020 11 4;587(7834):460-465. Epub 2020 Nov 4.

Cardiothoracic Surgery, Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK.

Atrial fibrillation, the most common cardiac arrhythmia, is an important contributor to mortality and morbidity, and particularly to the risk of stroke in humans. Atrial-tissue fibrosis is a central pathophysiological feature of atrial fibrillation that also hampers its treatment; the underlying molecular mechanisms are poorly understood and warrant investigation given the inadequacy of present therapies. Here we show that calcitonin, a hormone product of the thyroid gland involved in bone metabolism, is also produced by atrial cardiomyocytes in substantial quantities and acts as a paracrine signal that affects neighbouring collagen-producing fibroblasts to control their proliferation and secretion of extracellular matrix proteins. Global disruption of calcitonin receptor signalling in mice causes atrial fibrosis and increases susceptibility to atrial fibrillation. In mice in which liver kinase B1 is knocked down specifically in the atria, atrial-specific knockdown of calcitonin promotes atrial fibrosis and increases and prolongs spontaneous episodes of atrial fibrillation, whereas atrial-specific overexpression of calcitonin prevents both atrial fibrosis and fibrillation. Human patients with persistent atrial fibrillation show sixfold lower levels of myocardial calcitonin compared to control individuals with normal heart rhythm, with loss of calcitonin receptors in the fibroblast membrane. Although transcriptome analysis of human atrial fibroblasts reveals little change after exposure to calcitonin, proteomic analysis shows extensive alterations in extracellular matrix proteins and pathways related to fibrogenesis, infection and immune responses, and transcriptional regulation. Strategies to restore disrupted myocardial calcitonin signalling thus may offer therapeutic avenues for patients with atrial fibrillation.
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http://dx.doi.org/10.1038/s41586-020-2890-8DOI Listing
November 2020

Proteomic landscape of TGF-β1-induced fibrogenesis in renal fibroblasts.

Sci Rep 2020 11 4;10(1):19054. Epub 2020 Nov 4.

Renal Science and Integrative Chinese Medicine Laboratory, Department of Inflammation Biology, School of Immunology and Microbial Sciences, King's College London, London, UK.

Transforming growth factor-β1 (TGF-β1) plays a premier role in fibrosis. To understand the molecular events underpinning TGF-β1-induced fibrogenesis, we examined the proteomic profiling of a TGF-β1-induced in vitro model of fibrosis in NRK-49F normal rat kidney fibroblasts. Mass spectrometric analysis indicated that 628 cell-lysate proteins enriched in 44 cellular component clusters, 24 biological processes and 27 molecular functions were regulated by TGF-β1. Cell-lysate proteins regulated by TGF-β1 were characterised by increased ribosomal proteins and dysregulated proteins involved in multiple metabolic pathways, including reduced Aldh3a1 and induced Enpp1 and Impdh2, which were validated by enzyme-linked immunosorbent assays (ELISA). In conditioned media, 62 proteins enriched in 20 cellular component clusters, 40 biological processes and 7 molecular functions were regulated by TGF-β1. Secretomic analysis and ELISA uncovered dysregulated collagen degradation regulators (induced PAI-1 and reduced Mmp3), collagen crosslinker (induced Plod2), signalling molecules (induced Ccn1, Ccn2 and Tsku, and reduced Ccn3) and chemokines (induced Ccl2 and Ccl7) in the TGF-β1 group. We conclude that TGF-β1-induced fibrogenesis in renal fibroblasts is an intracellular metabolic disorder and is inherently coupled with inflammation mediated by chemokines. Proteomic profiling established in this project may guide development of novel anti-fibrotic therapies in a network pharmacology approach.
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http://dx.doi.org/10.1038/s41598-020-75989-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642370PMC
November 2020

Metabolic recovery after weight loss surgery is reflected in serum microRNAs.

BMJ Open Diabetes Res Care 2020 10;8(2)

King's British Heart Foundation Centre, School of Cardiovascular Medicine and Sciences, King's College London, London, UK

Introduction: Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue.

Research Design And Methods: We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up.

Results: Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction.

Conclusions: Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.
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http://dx.doi.org/10.1136/bmjdrc-2020-001441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594349PMC
October 2020

Fibroblast Nox2 (NADPH Oxidase-2) Regulates ANG II (Angiotensin II)-Induced Vascular Remodeling and Hypertension via Paracrine Signaling to Vascular Smooth Muscle Cells.

Arterioscler Thromb Vasc Biol 2021 02 15;41(2):698-710. Epub 2020 Oct 15.

King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine and Sciences, United Kingdom (C.B.H., S.C.T., D.A.R., C.X.C.S., G.S., X.Z., M.Z., A.C.B., X.Y., M.M., A.M.S.).

Objective: The superoxide-generating Nox2 (NADPH oxidase-2) is expressed in multiple cell types. Previous studies demonstrated distinct roles for cardiomyocyte, endothelial cell, and leukocyte cell Nox2 in ANG II (angiotensin II)-induced cardiovascular remodeling. However, the in vivo role of fibroblast Nox2 remains unclear. Approach and Results: We developed a novel mouse model with inducible fibroblast-specific deficiency of Nox2 (fibroblast-specific Nox2 knockout or Fibro-Nox2KO mice) and investigated the responses to chronic ANG II stimulation. Fibro-Nox2KO mice showed no differences in basal blood pressure or vessel wall morphology, but the hypertensive response to ANG II infusion (1.1 mg/[kg·day] for 14 days) was substantially reduced as compared to control Nox2-Flox littermates. This was accompanied by a significant attenuation of aortic and resistance vessel remodeling. The conditioned medium of ANG II-stimulated primary fibroblasts induced a significant increase in vascular smooth muscle cell growth, which was inhibited by the short hairpin RNA (shRNA)-mediated knockdown of fibroblast Nox2. Mass spectrometric analysis of the secretome of ANG II-treated primary fibroblasts identified GDF6 (growth differentiation factor 6) as a potential growth factor that may be involved in these effects. Recombinant GDF6 induced a concentration-dependent increase in vascular smooth muscle cell growth while chronic ANG II infusion in vivo significantly increased aortic GDF6 protein levels in control mice but not Fibro-Nox2KO animals. Finally, silencing GDF6 in fibroblasts prevented the induction of vascular smooth muscle cell growth by fibroblast-conditioned media in vitro.

Conclusions: These results indicate that fibroblast Nox2 plays a crucial role in the development of ANG II-induced vascular remodeling and hypertension in vivo. Mechanistically, fibroblast Nox2 may regulate paracrine signaling to medial vascular smooth muscle cells via factors, such as GDF6.
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http://dx.doi.org/10.1161/ATVBAHA.120.315322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837692PMC
February 2021

Extracellular matrix protein signature of recurrent spontaneous cervical artery dissection.

Neurology 2020 10 4;95(15):e2047-e2055. Epub 2020 Sep 4.

From the Departments of Neurology (L.M., R.P., C.B., T.T., J.W., S.K., M.K.), Neuroradiology (E.R.G.), Internal Medicine IV (P.P.), and Dermatology (G.R.), Medical University Innsbruck, Austria; King's British Heart Foundation Centre (J.B.-B., M.L., X.Y., M.M.), King's College London, London, UK; and VASCage (S.K.), Research Centre on Vascular Ageing and Stroke, Innsbruck, Austria.

Objective: To assess whether connective tissue disorder is evident in patients with spontaneous cervical artery dissection and therefore identify patients at risk of recurrence using a cutting-edge quantitative proteomics approach.

Methods: In the ReSect study, all patients with spontaneous cervical artery dissection treated at the Innsbruck University Hospital since 1996 were invited to attend a standardized clinical follow-up examination. Protein abundance in skin punch biopsies (n = 50) was evaluated by a cutting-edge quantitative proteomics approach (liquid chromatography-mass spectrometry) that has hitherto not been applied to such patients.

Results: Patients with 1-time single-vessel (n = 19) or multiple-vessel (n = 13) dissections did not differ between each other or compared to healthy controls (n = 12) in protein composition. Patients with recurrent spontaneous cervical artery dissection (n = 6), however, showed significantly different expression of 25 proteins compared to the other groups combined. Literature review and Gene Ontology term annotation check revealed that 13 of the differently expressed proteins play a major role in the structural integrity of connective tissue or are linked to connective tissue disorders. These proteins showed clustering to a collagen/elastin cluster and one consisting of desmosome related proteins.

Conclusion: This study unravels an extracellular matrix protein signature of recurrent spontaneous cervical artery dissection. In the long run and after large-scale validation, our findings may well assist in identifying patients at risk of recurrent spontaneous cervical artery dissection and thus guide therapy.
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http://dx.doi.org/10.1212/WNL.0000000000010710DOI Listing
October 2020

Right Ventricle Has Normal Myofilament Function But Shows Perturbations in the Expression of Extracellular Matrix Genes in Patients With Tetralogy of Fallot Undergoing Pulmonary Valve Replacement.

J Am Heart Assoc 2020 08 1;9(16):e015342. Epub 2020 Aug 1.

School of Cardiovascular Medicine and Sciences King's College London BHF Centre for Research Excellence London United Kingdom.

Background Patients with repair of tetralogy of Fallot (rToF) who are approaching adulthood often exhibit pulmonary valve regurgitation, leading to right ventricle (RV) dilatation and dysfunction. The regurgitation can be corrected by pulmonary valve replacement (PVR), but the optimal surgical timing remains under debate, mainly because of the poorly understood nature of RV remodeling in patients with rToF. The goal of this study was to probe for pathologic molecular, cellular, and tissue changes in the myocardium of patients with rToF at the time of PVR. Methods and Results We measured contractile function of permeabilized myocytes, collagen content of tissue samples, and the expression of mRNA and selected proteins in RV tissue samples from patients with rToF undergoing PVR for severe pulmonary valve regurgitation. The data were compared with nondiseased RV tissue from unused donor hearts. Contractile performance and passive stiffness of the myofilaments in permeabilized myocytes were similar in rToF-PVR and RV donor samples, as was collagen content and cross-linking. The patients with rToF undergoing PVR had enhanced mRNA expression of genes associated with connective tissue diseases and tissue remodeling, including the small leucine-rich proteoglycans ASPN (asporin), LUM (lumican), and OGN (osteoglycin), although their protein levels were not significantly increased. Conclusions RV myofilaments from patients with rToF undergoing PVR showed no functional impairment, but the changes in extracellular matrix gene expression may indicate the early stages of remodeling. Our study found no evidence of major damage at the cellular and tissue levels in the RV of patients with rToF who underwent PVR according to current clinical criteria.
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http://dx.doi.org/10.1161/JAHA.119.015342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660801PMC
August 2020

Very preterm birth results in later lower platelet activation markers.

Pediatr Res 2021 Apr 22;89(5):1278-1282. Epub 2020 Jul 22.

Department of Pediatrics II, Medical University of Innsbruck, Innsbruck, Tyrol, Austria.

Background: Premature birth entails an adverse cardiovascular risk profile, but the underlying mechanisms are insufficiently understood. Here, we employed an unbiased cardiovascular proteomics approach to profile former very preterm-born preschoolers.

Methods: This observational study investigated differences in plasma concentrations of 79 proteins, including putative cardiovascular biomarkers between very preterm- and term-born children on average 5.5 years old (53.1% male) using multiple-reaction monitoring mass spectrometry.

Results: Very preterm-born (n = 38; median gestational age 29.6 weeks) compared to term-born (n = 26; 40.2 weeks) children featured lower plasma concentrations of platelet factor 4 (PLF4; -61.6%, P < 0.0001), platelet basic protein (CXCL7; -57.8%, P < 0.0001), and hemoglobin subunit beta (-48.3%, P < 0.0001). Results remained virtually unchanged when adjusting for complete blood count parameters, including platelet count. Conversely, whole blood hemoglobin was higher (+7.62%, P < 0.0001) in preterm-born children.

Conclusions: Very preterm birth was associated with decreased markers of platelet activation among preschoolers. These findings are consistent with reduced platelet reactivity persisting from very preterm birth to a preschool age.

Impact: Former very preterm-born preschoolers featured reduced levels of platelet activation markers. While lower platelet reactivity in very preterm-born compared to term-born infants in the first days of life was established, it was unknown when, if at all, reactivity normalizes. The current study suggests that platelet hyporeactivity due to very preterm birth persists at least up to a preschool age. "Immaturity of the hemostatic system" may be a persistent sequel of preterm birth, but larger studies are needed to investigate its potential clinical implications.
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http://dx.doi.org/10.1038/s41390-020-1070-8DOI Listing
April 2021

Cardiac dysfunction in cancer patients: beyond direct cardiomyocyte damage of anticancer drugs: novel cardio-oncology insights from the joint 2019 meeting of the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart.

Cardiovasc Res 2020 09;116(11):1820-1834

Institute for Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.

In western countries, cardiovascular (CV) disease and cancer are the leading causes of death in the ageing population. Recent epidemiological data suggest that cancer is more frequent in patients with prevalent or incident CV disease, in particular, heart failure (HF). Indeed, there is a tight link in terms of shared risk factors and mechanisms between HF and cancer. HF induced by anticancer therapies has been extensively studied, primarily focusing on the toxic effects that anti-tumour treatments exert on cardiomyocytes. In this Cardio-Oncology update, members of the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart discuss novel evidence interconnecting cardiac dysfunction and cancer via pathways in which cardiomyocytes may be involved but are not central. In particular, the multiple roles of cardiac stromal cells (endothelial cells and fibroblasts) and inflammatory cells are highlighted. Also, the gut microbiota is depicted as a new player at the crossroads between HF and cancer. Finally, the role of non-coding RNAs in Cardio-Oncology is also addressed. All these insights are expected to fuel additional research efforts in the field of Cardio-Oncology.
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http://dx.doi.org/10.1093/cvr/cvaa222DOI Listing
September 2020

Cathepsin A contributes to left ventricular remodeling by degrading extracellular superoxide dismutase in mice.

J Biol Chem 2020 09 9;295(36):12605-12617. Epub 2020 Jul 9.

Klinik für Innere Medizin III, Universität des Saarlandes, Homburg/Saar, Germany

In the heart, the serine carboxypeptidase cathepsin A (CatA) is distributed between lysosomes and the extracellular matrix (ECM). CatA-mediated degradation of extracellular peptides may contribute to ECM remodeling and left ventricular (LV) dysfunction. Here, we aimed to evaluate the effects of CatA overexpression on LV remodeling. A proteomic analysis of the secretome of adult mouse cardiac fibroblasts upon digestion by CatA identified the extracellular antioxidant enzyme superoxide dismutase (EC-SOD) as a novel substrate of CatA, which decreased EC-SOD abundance 5-fold. , both cardiomyocytes and cardiac fibroblasts expressed and secreted CatA protein, and only cardiac fibroblasts expressed and secreted EC-SOD protein. Cardiomyocyte-specific CatA overexpression and increased CatA activity in the LV of transgenic mice (CatA-TG) reduced EC-SOD protein levels by 43%. Loss of EC-SOD-mediated antioxidative activity resulted in significant accumulation of superoxide radicals (WT, 4.54 μmol/mg tissue/min; CatA-TG, 8.62 μmol/mg tissue/min), increased inflammation, myocyte hypertrophy (WT, 19.8 μm; CatA-TG, 21.9 μm), cellular apoptosis, and elevated mRNA expression of hypertrophy-related and profibrotic marker genes, without affecting intracellular detoxifying proteins. In CatA-TG mice, LV interstitial fibrosis formation was enhanced by 19%, and the type I/type III collagen ratio was shifted toward higher abundance of collagen I fibers. Cardiac remodeling in CatA-TG was accompanied by an increased LV weight/body weight ratio and LV end diastolic volume (WT, 50.8 μl; CatA-TG, 61.9 μl). In conclusion, CatA-mediated EC-SOD reduction in the heart contributes to increased oxidative stress, myocyte hypertrophy, ECM remodeling, and inflammation, implicating CatA as a potential therapeutic target to prevent ventricular remodeling.
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http://dx.doi.org/10.1074/jbc.RA120.013488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476717PMC
September 2020

Platelet "-omics" in health and cardiovascular disease.

Atherosclerosis 2020 08 16;307:87-96. Epub 2020 Jun 16.

King's British Heart Foundation Centre, King's College London, 125 Coldharbour Lane, London, SE5 9NU, United Kingdom. Electronic address:

The importance of platelets for cardiovascular disease was established as early as the 19th century. Their therapeutic inhibition stands alongside the biggest achievements in medicine. Still, certain aspects of platelet pathophysiology remain unclear. This includes platelet resistance to antiplatelet therapy and the contribution of platelets to vascular remodelling and extends beyond cardiovascular disease to haematological disorders and cancer. To address these gaps in our knowledge, a better understanding of the underlying molecular processes is needed. This will be enabled by technologies that capture dysregulated molecular processes and can integrate them into a broader network of biological systems. The advent of -omics technologies, such as mass spectrometry proteomics, metabolomics and lipidomics; highly multiplexed affinity-based proteomics; microarray- or RNA-sequencing-(RNA-seq)-based transcriptomics, and most recently ribosome footprint-based translatomics, has enabled a more holistic understanding of platelet biology. Most of these methods have already been applied to platelets, and this review will summarise this information and discuss future developments in this area of research.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.05.022DOI Listing
August 2020

Noncoding RNAs versus Protein Biomarkers in Cardiovascular Disease.

Trends Mol Med 2020 06 12;26(6):583-596. Epub 2020 Mar 12.

King's British Heart Foundation Centre, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK. Electronic address:

The development of more sensitive protein biomarker assays results in continuous improvements in detectability, extending the range of clinical applications to the detection of subclinical cardiovascular disease (CVD). However, these efforts have not yet led to improvements in risk assessment compared with existing risk scores. Noncoding RNAs (ncRNAs) have been assessed as biomarkers, and miRNAs have attracted most attention. More recently, other ncRNA classes have been identified, including long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs). Here, we compare emerging ncRNA biomarkers in the cardiovascular field with protein biomarkers for their potential in clinical application, focusing on myocardial injury.
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http://dx.doi.org/10.1016/j.molmed.2020.02.001DOI Listing
June 2020

The Landscape of Coding and Noncoding RNAs in Platelets.

Antioxid Redox Signal 2021 05 25;34(15):1200-1216. Epub 2020 Jun 25.

King's British Heart Foundation Centre, King's College London, London, United Kingdom.

Levels of platelet noncoding RNAs (ncRNAs) are altered by disease, and ncRNAs may exert functions inside and outside of platelets. Their role in physiologic hemostasis and pathologic thrombosis remains to be explored. The number of RNA classes identified in platelets has been growing since the past decade. Apart from coding messenger RNAs, the RNA landscape in platelets comprises ncRNAs such as microRNAs, circular RNAs, long ncRNAs, YRNAs, and potentially environmentally derived exogenous ncRNAs. Recent research has focused on the function of platelet RNAs beyond platelets, mediated through protective RNA shuttles or even cellular uptake of entire platelets. Multiple studies have also explored the potential of platelet RNAs as novel biomarkers. Platelet preparations can contain contaminating leukocytes. Even few leukocytes may contribute a substantial amount of RNA. As biomarkers, platelet RNAs have shown associations with platelet activation, but it remains to be seen whether their measurements could improve diagnostics. It also needs to be clarified whether platelet RNAs influence processes beyond platelets. Technological advances such as single-cell RNA-sequencing might help to identify hyperreactive platelet subpopulations on a single-platelet level, avoid the common problem of leukocyte contamination in platelet preparations, and allow simultaneous profiling of native megakaryocytes and their platelet progeny to clarify to what extent the platelet RNA content reflects their megakaryocyte precursors or changes in the circulation. . 34, 1200-1216.
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http://dx.doi.org/10.1089/ars.2020.8139DOI Listing
May 2021

microRNAs as promising biomarkers of platelet activity in antiplatelet therapy monitoring.

Int J Mol Sci 2020 May 14;21(10). Epub 2020 May 14.

TAmiRNA GmbH, 1110 Vienna, Austria.

Given the high morbidity and mortality of cardiovascular diseases (CVDs), novel biomarkers for platelet reactivity are urgently needed. Ischemic events in CVDs are causally linked to platelets, small anucleate cells important for hemostasis. The major side-effect of antiplatelet therapy are life-threatening bleeding events. Current platelet function tests are not sufficient in guiding treatment decisions. Platelets host a broad spectrum of microRNAs (miRNAs) and are a major source of cell-free miRNAs in the blood stream. Platelet-related miRNAs have been suggested as biomarkers of platelet activation and assessment of antiplatelet therapy responsiveness. Platelets release miRNAs upon activation, possibly leading to alterations of plasma miRNA levels in conjunction with CVD or inadequate platelet inhibition. Unlike current platelet function tests, which measure platelet activation ex vivo, signatures of platelet-related miRNAs potentially enable the assessment of in vivo platelet reactivity. Evidence suggests that some miRNAs are responsive to platelet inhibition, making them promising biomarker candidates. In this review, we explain the secretion of miRNAs upon platelet activation and discuss the potential use of platelet-related miRNAs as biomarkers for CVD and antiplatelet therapy monitoring, but also highlight remaining gaps in our knowledge and uncertainties regarding clinical utility. We also elaborate on technical issues and limitations concerning plasma miRNA quantification.
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http://dx.doi.org/10.3390/ijms21103477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278969PMC
May 2020

Towards standardization of echocardiography for the evaluation of left ventricular function in adult rodents: a position paper of the ESC Working Group on Myocardial Function.

Cardiovasc Res 2021 01;117(1):43-59

Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Echocardiography is a reliable and reproducible method to assess non-invasively cardiac function in clinical and experimental research. Significant progress in the development of echocardiographic equipment and transducers has led to the successful translation of this methodology from humans to rodents, allowing for the scoring of disease severity and progression, testing of new drugs, and monitoring cardiac function in genetically modified or pharmacologically treated animals. However, as yet, there is no standardization in the procedure to acquire echocardiographic measurements in small animals. This position paper focuses on the appropriate acquisition and analysis of echocardiographic parameters in adult mice and rats, and provides reference values, representative images, and videos for the accurate and reproducible quantification of left ventricular function in healthy and pathological conditions.
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http://dx.doi.org/10.1093/cvr/cvaa110DOI Listing
January 2021

Extracellular Matrix in Vascular Disease, Part 2/4: JACC Focus Seminar.

J Am Coll Cardiol 2020 05;75(17):2189-2203

The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia; St. Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia. Electronic address:

Medium-sized and large arteries consist of 3 layers: the tunica intima, tunica media, and tunica adventitia. The tunica media accounts for the bulk of the vessel wall and is the chief determinant of mechanical compliance. It is primarily composed of circumferentially arranged layers of vascular smooth muscle cells that are separated by concentrically arranged elastic lamellae; a form of extracellular matrix (ECM). The tunica media is separated from the tunica intima and tunica adventitia, the innermost and outermost layers, respectively, by the internal and external elastic laminae. This second part of a 4-part JACC Focus Seminar discusses the contributions of the ECM to vascular homeostasis and pathology. Advances in genetics and proteomics approaches have fostered significant progress in our understanding of vascular ECM. This review highlights the important role of the ECM in vascular disease and the prospect of translating these discoveries into clinical disease biomarkers and potential future therapies.
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http://dx.doi.org/10.1016/j.jacc.2020.03.018DOI Listing
May 2020

Platelet Reactivity in Individuals Over 65 Years Old Is Not Modulated by Age.

Circ Res 2020 07 27;127(3):394-396. Epub 2020 Apr 27.

From the The Blizard Institute, Barts and The London School of Medicine ' Dentistry, Queen Mary University of London (M.V.C., P.C.A., T.D.W.).

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http://dx.doi.org/10.1161/CIRCRESAHA.119.316324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360093PMC
July 2020

Circulating MicroRNA Levels Indicate Platelet and Leukocyte Activation in Endotoxemia Despite Platelet P2Y Inhibition.

Int J Mol Sci 2020 Apr 21;21(8). Epub 2020 Apr 21.

King's British Heart Foundation Centre, King's College London, London SE5 9NU, UK.

There is evidence for the effects of platelet inhibition on innate immune activation. Circulating microRNAs (miRNAs) have been implicated as markers of platelet and leukocyte activation. In the present study, we assessed the effects of P2Y inhibitors on platelet and leukocyte miRNAs during endotoxemia. Healthy volunteers were randomly assigned to receive oral ticagrelor ( = 10), clopidogrel ( = 8) or no drug ( = 8) for one week, followed by an intravenous bolus of 2 ng/kg endotoxin. Serum was collected at baseline, after one week of antiplatelet treatment and 6 and 24 h after endotoxin administration. MiRNAs were screened using LNA-based qPCR, followed by TaqMan-qPCR validation of candidates. Clinical validation was performed in 41 sepsis patients. Platelet-enriched miR-197, miR-223 and miR-223* were decreased in volunteers following antiplatelet therapy. Endotoxin increased platelet miRNAs, whilst the opposite effect was seen for leukocyte-enriched miR-150. Neither of these endotoxin-mediated effects were altered by P2Y inhibitors. Sepsis patients with fatal outcomes ( = 12) had reduced miR-150 levels compared with survivors ( = 29). In conclusion, we show that miR-150 is downregulated in experimental endotoxemia and can predict survival in sepsis but is unaffected by P2Y inhibition. While P2Y inhibition reduces platelet-associated miRNAs in healthy volunteers, it fails to attenuate the response of platelet miRNAs to endotoxemia.
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http://dx.doi.org/10.3390/ijms21082897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215420PMC
April 2020

The 'Digital Twin' to enable the vision of precision cardiology.

Eur Heart J 2020 12;41(48):4556-4564

Department of Engineering Science, University of Oxford, Oxford, UK.

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.
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http://dx.doi.org/10.1093/eurheartj/ehaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774470PMC
December 2020

Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration.

Circulation 2020 04 11;141(15):1249-1265. Epub 2020 Feb 11.

Cardiovascular Research Center (A.M, N.S., A.A.K., I.M., T.M. K.B., M.T.K.S., E.C., Y.S., J.G.O., P.L, A.G.-S., C.K., M.M., L.Z.), Icahn School of Medicine at Mount Sinai, New York.

Background: The adult mammalian heart has limited regenerative capacity, mostly attributable to postnatal cardiomyocyte cell cycle arrest. In the last 2 decades, numerous studies have explored cardiomyocyte cell cycle regulatory mechanisms to enhance myocardial regeneration after myocardial infarction. Pkm2 (Pyruvate kinase muscle isoenzyme 2) is an isoenzyme of the glycolytic enzyme pyruvate kinase. The role of Pkm2 in cardiomyocyte proliferation, heart development, and cardiac regeneration is unknown.

Methods: We investigated the effect of Pkm2 in cardiomyocytes through models of loss (cardiomyocyte-specific Pkm2 deletion during cardiac development) or gain using cardiomyocyte-specific Pkm2 modified mRNA to evaluate Pkm2 function and regenerative affects after acute or chronic myocardial infarction in mice.

Results: Here, we identify Pkm2 as an important regulator of the cardiomyocyte cell cycle. We show that Pkm2 is expressed in cardiomyocytes during development and immediately after birth but not during adulthood. Loss of function studies show that cardiomyocyte-specific Pkm2 deletion during cardiac development resulted in significantly reduced cardiomyocyte cell cycle, cardiomyocyte numbers, and myocardial size. In addition, using cardiomyocyte-specific Pkm2 modified RNA, our novel cardiomyocyte-targeted strategy, after acute or chronic myocardial infarction, resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. We mechanistically show that Pkm2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and β-catenin.

Conclusions: We demonstrate that Pkm2 is an important intrinsic regulator of the cardiomyocyte cell cycle and oxidative stress, and highlight its therapeutic potential using cardiomyocyte-specific Pkm2 modified RNA as a gene delivery platform.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241614PMC
April 2020

Expression in Vascular Endothelial Cells Is Modulated by a Coronary Artery Disease-Associated Genetic Variant and Influences Monocyte Transendothelial Migration.

J Am Heart Assoc 2020 02 11;9(4):e014333. Epub 2020 Feb 11.

Shantou University Medical College Shantou China.

Background Genome-wide association studies have shown an association between the single-nucleotide polymorphism on chromosome 15q26.1 and coronary artery disease susceptibility. The underlying biological mechanism is, however, not fully understood. is located in the FES Upstream Region () gene, which is expressed in vascular endothelial cells (ECs). We investigated whether has an influence on expression in ECs and whether FURIN affects EC behavior. Methods and Results Quantitative reverse transcription-polymerase chain reaction analysis showed that cultured vascular ECs from individuals carrying the coronary artery disease risk allele of had higher expression than cells from noncarriers. In support, luciferase reporter analyses in ECs indicated that the risk allele had higher transcriptional activity than the nonrisk allele. Electrophoretic mobility shift assays using EC nuclear protein extracts detected a DNA-protein complex with allele-specific differential binding of a nuclear protein. Knockdown of FURIN in ECs reduced endothelin-1 secretion, nuclear factor-κB activity, vascular cell adhesion molecule-1, and MCP1 (monocyte chemotactic protein-1) expression and monocyte-endothelial adhesion and transmigration. A population-based study showed an association of the risk allele with higher circulating MCP1 levels and greater carotid intima-media thickness. Conclusions The coronary artery disease risk variant at the 15q26.1 locus modulates expression in vascular ECs. FURIN levels in ECs affect monocyte-endothelial adhesion and migration.
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http://dx.doi.org/10.1161/JAHA.119.014333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070217PMC
February 2020
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