bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postnatal overfeeding in mice induces early lipidic changes in heart tissue and impacts cardiomyocyte proliferation
Authors: Josse M , Rigal E , Rosenblatt N , Rochais F , Pais De Barros J P , Rochette L , Vergely C 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): French Federation of Cardiology
Foundation of France

Background
Shortly after birth, cardiomyocytes lose their ability to proliferate to switch towards a hypertrophic growth and this ability is known to be influenced by nutritional factors. Postnatal overfeeding (PNOF) induced by litter size reduction in rodents reproduces the impact of childhood overnutrition. While PNOF was shown to induce major cardiac and metabolic alterations in adulthood, little is known about its impact during the first days of life.

Purpose
The objective of this project was to investigate the early changes induced by PNOF induced in heart tissue in terms of lipid profile and cardiomyocyte proliferation.

Methods
Two days after birth, C57BL/6 male pups were randomly distributed in litters adjusted to either 9 or 3 pups to form normally fed (NF) or postnatally overfed (PNOF) group, respectively. At 7, 10 and 24 postnatal days (D7, D10 and D24, respectively), hearts were harvested for immunostaining of the proliferation marker Ki67. Cardiac and plasma lipid composition of NF and PNOF was evaluated using liquid chromatography coupled to mass spectrometry technique. Finally, cardiomyocytes from D24 hearts were isolated and counted on Malassez counting chamber.

Results
At D7, D10 and D24, body weight and cardiac mass of PNOF pups were significantly higher than these of NF controls. Interestingly, at D7, lipid composition of PNOF hearts was decreased in cardiolipins, fatty acids and cholesterol derivatives. Moreover, plasma triglyceride levels were lower in D10 PNOF pups. These modifications were associated with a significant reduction of cardiomyocytes’ proliferation rate and an increased hypertrophy in PNOF hearts at D7, resulting in the reduction of cardiomyocyte number at D24 in PNOF mice.

Conclusion
Only five days after litter size reduction, PNOF induced major lipidic changes both in the cardiac tissue and in the plasma. In parallel, PNOF shortened the cardiomyocyte proliferative window and induced earlier cardiomyocyte maturation. Given the importance of fatty acid metabolism in cardiac development and function, these early changes could be linked to the long-term cardiometabolic alterations observed later in life.
The role of serotonin receptor 7 signalling in macrophages for the inflammatory response after myocardial infarction
Authors: Bahr F S , Mueller F E , Weber N , Aguapong W , Neumueller S , Benen N , Ricke-Hoch M , Ponimaskin E 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Background
The hormone and neurotransmitter serotonin regulates multiple processes, including immune responses and inflammatory signalling. After a cardiac injury, such as myocardial infarction (MI), a precise regulation of the local inflammation is determining the healing process and therefore functional outcome. Immune cells invading the infarcted tissue can be critical modulators, and various immune cells, including macrophages, express different serotonin receptors.

Purpose
We characterized the importance of serotonin receptor 7 (5-HT7R) signalling in the regulation of macrophage function, which infiltrate the heart after MI and thus can determine the course of cardiac remodelling processes.

Methods
For investigation of 5-HT7R signalling on a cellular level, we used two in vitro models: primary murine bone marrow-derived macrophages (BMDM) and secondary human THP-1-derived macrophages. To validate the impact of macrophages on intact cardiac tissue, we pre-treated pro-inflammatory M1-like BMDMs with a selective 5-HT7R agonist and then co-cultured them with living cardiac rat slices for up to 48 h (ex vivo) followed by functional analysis.

Results
We detected 5-HT7R expression in both models during all stages of macrophage polarization at mRNA as well as protein levels. Pro-inflammatory THP-1-derived macrophages displayed significantly enhanced mRNA expression levels of IL-1β and CD80, while pro-inflammatory differentiated M1-like BMDMs showed increased levels of CD38 and TNFα. Pharmacological activation of 5-HT7R with LP-211 reduced phagocytic activity up to 4-fold in THP-1-derived pro-inflammatory macrophages, altered their cytokine secretion profile and inhibited their migration ability (recovered area in scratch assay 1.3 % after LP-211 treatment compared to 6.1 % in control). A reduction in phagocytic activity was also verified in pro-inflammatory BMDMs. Our results also indicate reduced ability of LP-211 treated M1-like BMDMs to infiltrate living cardiac slices 3, 12, 24 and 48 h after seeding.

Conclusion
5-HT7R signalling affects the functional properties of pro-inflammatory macrophages, including phagocytic activity, motility and secretion profile. Targeted manipulation of 5-HT7R activity in macrophages represents thus a possibility to modulate their inflammatory profile, which might be a reasonable approach to guide recovery post MI.
Increased perivascular fibrosis and pro-fibrotic cellular transition in intramyocardial blood vessels in patients with myocardial infarction
Authors: Jiang Z , Sorrentino G , Simsek S , Niessen H W M , Krijnen P A J 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): China Scholarship Council

Background
Myocardial infarction (MI) is pathologically characterized by irreversible myocardial necrosis caused by ischemia. Intramyocardial vascular dysfunction is believed to increase the risk of MI. In this study, we investigated intramyocardial blood vessels in deceased patients during the early and chronic phases of MI to explore the involvement of perivascular fibrosis and pro-fibrotic cellular transitions in the pathological process of MI.

Methods
Left ventricular tissue (LV) was obtained from the infarction area of autopsied patients with early-phase MI (3-6 hours old; n=23), chronic-phase MI (5-14 days old; n=12), and from non-infarcted controls (n=14). We quantified perivascular fibrosis using EVG staining and fibroblast activation protein (FAP) expression using immunohistochemistry. Co-localization of smooth muscle actin (SMA) or CD31 with fibroblast marker S100A4 indicative of transition of smooth muscle cells (SMC) and endothelial cells (EC) toward fibroblast-like cells in intramyocardial vessels was quantified using immunofluorescent microscopy.

Results
Compared to controls (61.03%), perivascular fibrosis was significantly elevated in MI patients (early-phase 77.20%; chronic-phase 82.58%)(p&lt;0.0001), with the highest level observed in the infarct cores of chronic-phase patients (95.18%). Compared to controls, FAP expression was 3.5-fold higher in early-phase- and 15.3-fold higher in chronic-phase MI patients (p&lt;0.05), wherein FAP expression again was highest in the infarct cores. Furthermore, in both early- and chronic-phase MI, SMC- and EC fibroblast-like cellular transition was increased. The fraction of SMA+S100A4+ vessels was significantly higher in early-phase MI (31.96%) and chronic-phase MI (21.9%: border zone; 37.25%: infarct core) compared to controls (8.95%)(p&lt;0.05). Similarly, the fraction of CD31+S100A4+ area was significantly increased in early-phase MI (10.14%) and chronic-phase MI (8.31%: border zone 10.15%: infarct core) compared to controls (2.67%)(p&lt;0.05).

Conclusion
We observed increased perivascular fibrosis, fibroblast activation and fibroblast-like cellular transition toward a pro-fibrotic phenotype of vascular cells in intramyocardial blood vessels in MI patients, that may contribute to the development of MI. The further increase of FAP expression and perivascular fibrosis, particularly in the infarct core, in the chronic-phase suggest that MI itself can exacerbate fibroblast activation and perivascular fibrosis, theoretically increasing the risk of reinfarction.FAP expression and perivascular fibrosispro-fibrotic vascular cellular transitio
Sex differences in cardiac ferroptosis after acute myocardial infarction in wild type and aryl hydrocarbon receptor knockout mice
Authors: Delgado C , Fedichkina R , Martin-Nunes L , Piedras M J , Ramiro-Ponce V , Alvarez-Lucena C , Gil-Fernandez M , Fernandez-Velasco M , Bosca L 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – EU funding. Main funding source(s): MICIN/Agencia Estatal de Investigación (DOI: 10.13039/50110001103) (NextGeneration, EU/PRTR)

Background and Purpose
Ferroptosis is a new regulated programmed cell death pathway, driven by iron-dependent phospholipid peroxidation, that plays an important role in the development of cardiovascular diseases. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor of the basic Helix-Loop-Helix-PER-ARNT-SIM superfamily. Upon ligand binding, AhR translocates into the nucleus and dimerizes with the AhR nuclear translocator; the heterodimer then binds to dioxin-response elements located in the promoter region of receptor-regulated genes, most of which are involved in xenobiotic metabolism. Beyond its role in metabolizing exogenous toxins as part of an adaptive chemical response, it is well known that AhR is activated by endogenous ligands and it has been postulated that AhR has important functions in physiological and/or pathological conditions. Here we studied sex differences in cardiac ferroptosis after acute myocardial infarction (AMI) in mice and the implication of defective AhR signalling on this process.

Methods and Results
AMI was induced in 8–10-weeks-old males and females AhR+/+ and AhR-/- mice by ligation of the left anterior descending coronary artery. Animal care and experimental procedures followed the principles of animal care (NIH publication Nº85-23 revised 1985) and the guidelines for ethical care of experimental animals of the European Union (2010/63/EU). Survival analysis showed that 16% of AhR+/+male mice and 14% of AhR+/+ female mice died 72 h after AMI surgery whereas the mortality was 100% in AhR-/-male mice and only 17% in AhR-/- female mice group. The treatment of AhR-/- AMI male mice with ferrostatin (1 mg/kg i.p) increased survival to 40%. Immunofluorescence analysis of cardiac staining levels of 8-hydroxy-2’-deoxyguanosine revealed higher oxidative stress in AhR+/+AMI male mice compared with AhR+/+AMI females, 24 h after surgery. The absence of AhR in AMI males showed an increased oxidative stress that was similar to that obtained in AMI AhR+/+ males but significantly greater than that observed in AhR-/- AMI females. Finally, analysis of differential expressions of classical genes related to ferroptosis in AhR-/- AMI male and AMI female mice, 24 h after surgery, showed, only in males, a reduced expression of ferritin heavy chain 1 and ferroportin, and an increased expression of phospholipase A2.

Conclusion
Our results show that loss of AhR in males but not in females favours the ferroptosis process associated with myocardial ischemia, highlighting a possible role for this nuclear receptor in cardiac remodelling and survival after AMI.
Epicardial cell participation in cardiac repair requires epithelial-to-mesenchymal transition
Authors: Smits A M , Streef T J , Van Herwaarden T , Balbi C , Vegh A , Groeneveld E , Goumans M J 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation
During development, the epicardium forms as a single cell layer on the outside of the heart. Part of these cells undergo epithelial-to-mesenchymal transition (EMT) and migrate into the myocardium where epicardial-derived cells (EPDCs) participate in the formation of the heart by contributing cells and by producing paracrine factors. In the adult heart the epicardium exists as a dormant layer until there is ischemic injury which leads to a partial reactivation and participation in the repair process. Therefore, the epicardium is considered an interesting cell source for endogenous cardiac repair.

Aim
to establish if differences between developmental and adult epicardium exist, and in which state (pre- or post-EMT) epicardial cells contribute efficiently to cardiac repair.

Methods
Primary epicardial cells were isolated from human fetal and adult cardiac tissue samples and cultured as epicardial cells (EPIs) or as EPDCs after inducing EMT with TGFβ3. Cells were subjected to RNA-sequencing or 24hrs of conditioning medium. Myocardial infarction (MI) and intramyocardially injection of EPIs and EPDCs was performed in NOD-SCID mice.

Results
Fetal and adult EPDCs displayed similar transcriptomic and paracrine profiles. In vitro, the conditioned medium of both cell types equally conveyed cardioprotection to staurosporin-treated cardiomyocytes. Next, we studied the effect of EMT: comparison of adult EPIs with EPDCs revealed that EPDCs have a angiogenic profile. Six weeks post-MI transplantation of adult EPIs or EPDCs resulted in a higher EF (25.4±3.8 vs. 11.1±4.6%, P&lt;0.005), lower ESV (139.6±13.5 vs, 91.37±14.2ul, P&lt;0.05), and a smaller infarct size in EPDC-recipients. EPDC-recipient hearts contained more proliferating cells at 3 days, and a higher vessel density at 6wks post-MI. Interestingly, while cell engraftment was equal in both groups at 3days, no cells were retrieved at 6wks supporting a paracrine effect.

Conclusion
epicardial EMT is essential to unleash the predominantly paracrine contribution of epicardial cells in cardiac repair.
Targeting serotonin receptor 7 to improve survival after myocardial infarction
Authors: Mueller F , Erschow S , Bahr F S , Benen N , Ponimaskin E , Ricke-Hoch M 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Deutsche Forschungsgemeinschaft (DFG)

Background
Myocardial infarction (MI) is among the leading causes of death worldwide. Survival and long-term recovery are highly dependent on regeneration of the cardiac tissue, mediated by precisely regulated inflammatory processes and invading immune cells. The serotonergic system is known to regulate the functions of various cells of the immune system, and is also affected in several cardiovascular diseases.

Purpose
We investigated the role of the serotonin receptor 7 (5-HT7R) in regulation of the inflammatory response after MI and its contribution to cardiac outcome.

Methods
Permanent left ascending coronary artery ligation (LAD) in mice was used as a model for MI. We compared the impact of MI on heart function and tissue integrity in WT and 5-HT7R-KO mice. In addition, we performed a systemic treatment with the selective 5-HT7R agonist LP-211.

Results
Murine C57BL/6N hearts reveal an upregulation of 5-HT7R mRNA expression in the infarct region compared to remote myocardium and sham operated mice at 3, 7 and 14 days after MI. Immunohistochemistry demonstrates 5-HT7R expression mainly on CD68+, CD206+ and CD80+ macrophages but not on cardiomyocytes and fibroblasts. Systemic 5-HT7R-KO mice display normal cardiac function and dimensions at 3-4 months of age comparable to their wildtype (WT) littermates. In response to MI, 5-HT7R-KO mice show a higher decrease in left ventricular (LV) function (assessed by transthoracic echocardiography as fractional area change, FAC%) and increased signs of tissue inflammation 14 days post-MI, while the infarct size remains unchanged. Interestingly, systemic treatment with the selective 5-HT7R agonist LP-211 enhances survival rates 14d post MI, without improving cardiac functional output.

Conclusion
5-HT7R expression is upregulated post-MI in heart-invading inflammatory cells, such as macrophages. Loss of systemic 5-HT7R may contribute to pronounced functional cardiac impairment 14 days after MI, while systemic activation of 5-HT7R shows positive effects on survival, possibly through mediated inflammatory signalling of immune cells. Therefore, 5-HT7R activity could represent a novel therapeutic target to dampen inflammation and improve cardiac repair.
The diabetic myocardial transcriptome reveals Erbb3 as a novel biomarker of incident heart failure
Authors: Conning-Rowland M , Giannoudi M , Drozd M , Brown O , Yuldasheva N , Cheng C , Meakin P , Straw S , Gierula J , Ajjan R , Kearney M , Levelt E , Roberts L , Griffin K , Cubbon R 
Published: May 2024

Abstract

Funding Acknowledgements
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): British Heart Foundation

Background/Introduction
People with diabetes mellitus (DM) are at high risk of developing heart failure, but the molecular basis of this is not well understood. Elucidating the mechanistic pathways may help to improve patient stratification and develop targeted therapies.

Purpose
We set out to define differentially expressed genes (DEGs) in diabetic myocardium and validate arising hits in their circulating protein form, with a view to informing biomarker development and improving understanding of diabetic heart disease.

Methods
Transcriptomic (RNA-seq) data from the Genotype-Tissue Expression (GTEx) project was used to compare gene expression in participants with (n=&gt;100) versus without (n&gt;300) DM (pooled type 1 and 2 diabetes mellitus), in both the right atrial (RA) and left ventricular (LV) myocardium; analyses were adjusted for technical, demographic and disease covariates. Where available, plasma proteomic data from the UK Biobank (UKB) cohort was used to validate DEGs from GTEx in their circulating protein form. Hits with directionally concordant differential expression in GTEx and UKB were further characterised as plasma proteins in UKB, including over 50,000 participants irrespective of DM status; this included analysis of incident heart failure, cardiovascular mortality and left ventricular function on cardiac magnetic resonance imaging.

Results
Pooled across the RA and LV, there were 64 DEGs associated with DM, with no overlap between the RA and LV hits. UKB plasma protein data was available for 6 of these. Only ERBB3 showed directional concordance with transcriptomic data, being lower in the myocardium and blood of people with DM. People in the lowest quartile of ERBB3 plasma protein had increased adjusted risk of incident heart failure and cardiovascular death than participants in all other quartiles. Lower concentrations of plasma ERBB3 protein were also associated with increased LV mass and impaired LV contractility.

Conclusion
Lower plasma ERBB3 concentration is more common in people with DM and is associated with LV dysfunction, incident heart failure and cardiovascular mortality. This highlights the potential of ERBB3 as a novel biomarker for individuals at risk of heart failure. Importantly, cancer therapies targeting ERBB3 and related family members can induce heart failure, and recombinant forms of the ERBB3 ligand neuregulin-1 appear to improve LV contractility, further suggesting a role of ERBB3 in the development of diabetic heart disease.
Deeper insights into heart failure with preserved ejection fraction through rna-sequencing of circulating endothelial cells - advanced protocol establishment enables complete transcriptome analysis
Authors: Wurmbrand L , Kalies K , Knoepp K , Dutzmann J , Sedding D 
Published: May 2024

Abstract
Funding Acknowledgements
None.
Heart failure with preserved ejection fraction (HFpEF) continues to pose a significant challenge with a bleak prognosis and a rising incidence, particularly among the aging population in Western countries. An in-depth comprehension of cellular-level pathogenesis, with a specific emphasis on the pivotal role of cellular senescence in endothelial dysfunction, is imperative for the evolution of innovative therapeutic interventions. Many previous approaches to investigate the genesis of HFpEF are based only on HFpEF-mouse models, which cannot directly be transferred to humans. The isolation of circulating endothelial cells from peripheral blood samples represents a more translatable, feasible, less invasive way to study endothelial dysfunction, a central component of HFpEF-pathogenesis, in human material for the identification of new therapeutical targets.
This study focuses on establishing a new protocol for isolating circulating endothelial cells (CEC) in HFpEF patients to address endothelial dysfunction and pinpoint novel therapeutic targets through a comprehensive whole transcriptome analysis. Methodologically, CEC isolation from whole blood samples was achieved using a newly established Fluorescence-Activated Cell Sorting (FACS) panel. HFpEF patients were recruited based on their HFA-PEFF score, with non-diseased controls comprising both young and old subjects meticulously matched for sex and age. Subsequently, the isolated CECs were subjected to transcriptome analysis.
Our new protocol is based on red blood cell lysis followed by magnetic cell sorting to deplete CD45+ cells. This is followed by staining with fluorescent-conjugated monoclonal antibodies. This FACS panel includes known endothelial-specific markers including CD11b- and CD45-, CD146+, CD34+ and CD31+ as well as DAPI- as a nucleus marker. The prepared CECs were sorted using FACS and a specially developed gating. We isolated the RNA in preparation for sequencing. Our protocol was validated by immunofluorescence staining of isolated CECs (markers: CD31, vWF, CD146, Phalloidin) and PCR analysis (markers: CD31, CD146 and vWF).
In summary, we have successfully established a new, robust and highly targeted workflow for consistently isolating circulating endothelial cells from blood and performing RNA sequencing on the collected samples. This is a key advance towards a deeper understanding of the pathophysiology of HFpEF. The application of our methodology may enable the characterization of patients with HFpEF at the transcriptome level. The whole transcriptome analyses provide potential starting points for further in vitro and in vivo studies. As we extend our investigations to larger patient cohorts in the future, there is potential for the identification of novel therapeutic targets.