bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fibroblast-specific SOCS3 deficient mice exhibits decreased myocardial fibrosis and increased cardiomyocyte survival after acute myocardial infarction
Authors: Okabe K , Yasukawa H , Sasaki T , Takahashi J , Nohara S , Shibata T , Yanai T , Akagaki D , Shibao K , Yamamoto M , Shima K , Fukumoto Y 
Published: November 2023

Abstract

Background
Left ventricular (LV) remodeling after acute myocardial infarction (AMI) results in poor cardiac performance leading to heart failure. LV remodeling after AMI is characterized by infarct expansion, LV dilation, and fibrosis of viable myocardium. Suppressor of cytokine signaling-3 (SOCS3) is an endogenous negative-feedback regulator of the STAT3 signaling pathway. We previously reported that myocardial SOCS3 plays a detrimental role in LV remodeling after AMI; however, the role of STAT3 and SOCS3 within fibroblast in LV remodeling after AMI remains elusive.

Objective
The aim of this study is to clarify the role of STAT3 and SOCS3 within fibroblasts in LV remodeling during AMI in mice.

Methods
To investigate the role of STAT3 signaling and SOCS3 within fibroblast, we generated tamoxifen-induced fibroblast-specific SOCS3-deficient (fib-SOCS3 KO) mice. AMI was induced by permanent ligation of the left anterior descending artery in mice. After 2 weeks of induction with tamoxifen, histological evaluation by Hematoxylin Eosin staining and Picro-Sirius Red staining, cardiac function evaluation by echocardiography using a Vevo 3100 Echo Imaging System (Visual Sonics), and protein expression using Western blot analysis were performed.

Results
There was no significant difference in 2-week survival rate between fib-SOCS3 KO group and wild type (WT). Two weeks after AMI, ventricular weight was less in fib-SOCS3 KO mice compared to WT mice (p&lt;0.05). In terms of cardiac function, LV ejection fraction was predominantly increased in fib-SOCS3 KO mice compared with WT mice, as measured by the Area method (p&lt;0.05). There was no difference in LV end-diastolic area, but LV end-systolic area was significantly less in fib-SOCS3 KO mice than in WT mice. Histologically, residual viable myocardium in the infarcted area was greater in fib-SOCS3 KO mice compared with WT mice. The percentage of fibrotic area in the LV short-axis plane was significantly less in fib-SOCS3 KO mice than in WT mice. Western blot analysis revealed that phosphorylated-STAT3 tended to be elevated in fib-SOCS3 KO mice than in WT mice.

Conclusions
Our data suggest that STAT3 and SOCS3 within fibroblast may play an important role in the prevention of LV remodeling after AMI.
Role of long non-coding RNA Zeb2os in protection of the injured heart
Authors: Caliandro R , Boender A , Van Rooij E , Boink G J J , Giacca M , Christoffels V M , Gladka M M 
Published: November 2023

Abstract
Heart failure due to ischemic heart disease is one of the leading causes of death worldwide. Terminated vasculature and cardiomyocyte apoptosis due to myocardial infarction are critical events in infarct healing. Therefore, identifying factors that can enhance cardiac repair by restoring the capillary network and inhibiting cardiomyocyte death is of great significance. Accumulating evidence implies that long non-coding RNAs (lncRNAs) are potent regulators of cardiac development and disease.
Our preliminary data show the potential cardioprotective function of the long non-coding RNA Zeb2 opposite strand (Zeb2os). This lncRNA overlaps and is antisense to ZEB2 at the 5' splice site of an intron within the 5' UTR. Zeb2os was shown to prevent splicing of the intron containing an internal ribosome entry site (IRES) that increases translation of the ZEB2 transcript. In line with the known function of ZEB2, Zeb2os has pro-angiogenic and anti-apoptotic functions in different organs. However, its role in the heart still has to be determined.
Our results show that Zeb2os expression is decreased in cultured cardiomyocytes subjected to H2O2-mediated oxidative stress, which correlates with increased apoptosis and reduced antioxidant defence of cardiac muscle cells. AAV6-mediated overexpression of Zeb2os in hiPSC-derived cardiomyocytes protects from H2O2-induced apoptosis, suggesting it may have cardioprotective activity, possibly through regulating Zeb2 translation. Additionally, systemic AAV9-mediated delivery of Zeb2os to the mouse heart enhanced angiogenesis by increasing the number of proliferating endothelial cells. Moreover, RNA-sequencing of Zeb2os overexpressing hearts at baseline implicated Zeb2os in the regulation of numerous genes related to response to hypoxia.
In conclusion, we uncovered/identified Zeb2os as a new potential cardioprotective factor with pro-angiogenic and anti-apoptotic properties. We are currently investigating the effect of AAV9-mediated delivery of Zeb2os in a mouse model of cardiac ischemia to understand further its protective role in the injured heart, which is an essential step towards the development of improved therapies for ischemic heart disease.
The mesencephalic astrocyte-derived neurotrophic factor (MANF) as a novel regulator of post-infarction cardiac sympathetic hyperinnervation
Authors: Blok M , Van Gils J M , Boukens B J D , Kielbasa S M , Van Schendel B W , Schoones J W , Smits A M , Goumans M J T H , De Ruiter M C , Jongbloed M R M 
Published: November 2023

Abstract

Background
Excessive outgrowth of sympathetic nerve fibers (sympathetic hyperinnervation) around the infarcted myocardium is associated with ventricular arrhythmia and an increased risk of sudden cardiac death. Post-infarction, epicardial cells exit quiescence through epithelial-to-mesenchymal transition (EMT), resulting in the formation of epicardium-derived cells (EPDCs). EPDCs support cardiac repair through differentiation into various cardiac cell lineages, as well as secretion of paracrine factors that stimulate processes such as angiogenesis. Recently, we demonstrated that human EPDCs reinforce neurite outgrowth in vitro. Whether EPDCs regulate cardiac innervation through paracrine signaling and contribute to post-infarction sympathetic hyperinnervation is unknown.

Purpose
To identify epicardial paracrine factors post-infarction that are involved in nerve growth.

Methods
Single-cell RNA-sequencing (scRNA-seq) datasets capturing epicardial cells of the healthy and infarcted adult mouse heart were collected from published research articles and were integrated into one object using Seurat. A list of gene products of known involvement in biological processes related to nerve growth (675 unique entries in total) was compiled. Based on this list, differential gene expression analysis on data from the integrated scRNA-seq object was performed to uncover highly-expressed candidates in the epicardial cell population. Epicardial expression of a candidate paracrine factor was validated by immunohistochemistry in the infarcted mouse heart as well as in an adult human in vitro model of EPDC EMT by immunocytochemistry and transcriptomic analysis.

Results
In our integrated scRNA-seq object, we identified high expression of Manf in epicardial cells post-infarction. Consistent with this finding, immunohistochemistry showed that Manf was up-regulated in the infarcted area, borderzone area, and epicardial region situated close to the infarct, an area where also hyperinnervation is observed. In vitro, MANF transcript expression was significantly down-regulated (p&lt;0.01) in human EPDCs that were stimulated with TGFβ3 to induce EMT compared to EPDCs in which EMT was inhibited. In line with this, immunocytochemistry staining of MANF indicated that MANF expression was down-regulated in human EPDCs stimulated with TGFβ3.

Conclusion(s)
This study is the first to show that Manf is highly expressed in the epicardial region close to the infarct. In vitro, MANF is down-regulated in human adult EPDCs post-EMT. Future experiments will be directed toward determining the effect of MANF knockdown in human EPDC on neurite outgrowth in co-cultured human sympathetic neurons.MANF expression in human EPDCs after EMTManf expression after infarction
Fully automatic screening for atrial fibrillation using a photoplethysmography based wristband and a novel smart infrastructure
Authors: Abdelhamid K , Reissenberger P , Piper D , Koenig N , Hoelz B , Schlaepfer J , Gysler S , Mccullough H , Ramin-Wright S , Gabathuler A , Khandpur J , Meier M , Eckestein J 
Published: November 2023

Abstract

Background
Atrial Fibrillation (AF) is the leading cause of stroke, and its prevalence is expected to rise. While early detection is crucial in preventing thromboembolic events, its often asymptomatic and paroxysmal nature makes it challenging to capture using conventional electrocardiography (ECG). Photoplethysmography (PPG) enabled devices, such as smartwatches, allow continuous monitoring of the heart rhythm and accurate screening for AF.

Purpose
In this study, we aimed to build an IT-infrastructure for fully automated screening of AF in hospitalised patients at risk using a PPG-based wrist worn wearable device.

Methods
We conducted an investigator-initiated, prospective, clinical trial to evaluate the performance of a PPG-based wristband coupled to an automatic data process device hub in hospitalised patients. Participants with a CHA2DS2-VASc score of two or higher and no prior history of AF were eligible for the study. Consenting participants received a wristband with a built-in PPG sensor to be worn during the entire hospital stay. Data from the wristband was automatically transmitted, stored, analysed and visualised. When absolute arrhythmia (AA) was detected in the PPG signal, a subsequent seven-day Holter ECG was performed to confirm the diagnosis.

Results
A total of 346 patients were included in the analysis (age 72 ± 10 years; 175 females (50.6%); mean CHA2DS2-VASc score of 3.5 ± 1.3). No data was lost in the process. The mean monitoring time was 4.3 ± 4.4 days, 45.9% was evaluable. In twelve patients (3.5%, CI: 1.5% - 5.4%) absolute arrhythmia (AA) was detected in the PPG-signal. The mean screening time until first detection of AA was 14.7 ± 16.8 hours. The highest detection rate was observed within the first 24 hours of screening (p = 0.004) (Figure 1). The AA burden per hour was 1.9 times greater during the night (22:00 - 06:00) compared to the day (p = 0.003) (Figure 2). Of the 346 patients, 304 (87.9%) were compliant in wearing the wristband for the entire hospitalisation. In nine patients a Holter ECG was recorded, no AF was identified.

Conclusions
We successfully established an infrastructure for automated AF screening in hospitalised patients using wrist-worn PPG devices, enabling real-time visualisation of incoming data and facilitating therapeutic interventions with minimal delay. To our knowledge this is the first hospital to implement a fully automated AF screening infrastructure based on PPG devices. In a population at risk, AA was identified in 3.5% of all patients. The high compliance rate of the wearable device further supports its feasibility and utility in clinical practice.Figure 1:Time to first detection of AAFigure 2:Total AA burden per hour
From cells to circulating biomarker: BMP10 is a myocyte-secreted peptide with potential to detect atrial fibrillation
Authors: E Molina C , Sommerfeld L , Zeller T , Obergassel J , Wieboldt H , Conradi L , Reichenspurner H , Nikolaev V O , Kirchhof P , Fabritz L 
Published: November 2023

Abstract

Background
Early onset detection and recurrence prediction of atrial fibrillation (AF) may improve therapeutic decision-making, prognosis and long-term outcome. Plasma proteome analyses and mechanistic studies identified bone morphogenetic protein 10 (BMP10) as an atrial-specific secreted biomolecule for AF associated with reduced paired-like homeodomain transcription factor 2 (PITX2) expression.

Purpose
Our aim is 1) to confirm BMP10 synthesis and secretion by human atrial isolated myocytes, 2) to compare BMP10 secreted levels between right atrial, left atrial and left ventricular myocytes, and 3) to assess if BMP10 secretion is indeed associated with AF in human myocytes.

Methods
Right atrial (RA), left atrial (LA) and left ventricular (LV) myocytes were isolated from 16 tissues samples of patients undergoing open heart surgery which were currently in sinus rhythm (SR) or AF. Freshly isolated myocytes were resuspended in minimal essential medium (MEM, M1) containing fetal bovine serum (FBS) and plated in laminin coated dishes. M1 was collected after 3 hours of culture and substituted by FBS-free medium (M2), which was collected after 48 hours of culture. Cardiomyocyte-released BMP10 levels were measured in M1 and M2 by ELISA.

Results
Cardiomyocytes from twelve patients (68±2.7 years, 52±2.1 % ejection fraction, 17 % women, 50 % with AF, 50 % valvular surgery and 75 % bypass) were cultured and BMP10 secreted levels analyzed. BMP10 concentrations were high in medium from atrial cardiomyocytes (2.76±1.8 ng/µl) and negligible in medium from ventricular cardiomyocytes (0.01±0.005 ng/µl). Left atrial cardiomyocytes released less BMP10 than right atrial cardiomyocytes (LA 0.02±0.007 ng/µl; RA 3.50±2.3 ng/µl). In addition, BMP10 concentrations were higher in right atrial cardiomyocytes from patients with AF (3.76±3.6 ng/µl) than in the right atrial cardiomyocytes from patients in SR (0.97±0.9 ng/µl).

Conclusion
Our results provide a direct proof that BMP10 is secreted by human atrial myocytes, mainly right atrial myocytes. Furthermore, atrial myocytes from patients with AF secreted significantly more BMP10 than myocytes from patients in sinus rhythm. These observations validate the atrial cardiomyocyte origin of circulating BMP10, making BMP10 a potentially attractive atrial-specific cardiac biomarker.
Regulatory roles of the N6-methyladenosine demethylase FTO in cardiac remodeling
Authors: Annamalai K , Buchholz E , Castro R , Panyam N , Fischer A , Toischer K 
Published: November 2023

Abstract

Background
The most prevalent internal RNA modification, N6-methyladenosine (m6A), serves as an additional layer of transcriptional and translational regulation. Methyl transferases (like METTL3) and demethylases (e.g., FTO) are the enzymes that catalyze m6A methylations. Our result showed that loss of FTO causes maladaptive cardiac remodeling in rodent hearts, which is consistent with other studies that emphasized the importance of FTO-dependent m6A RNA methylation in maintaining cardiac homeostasis, ventricular hypertrophy, and heart failure. Despite the fact that FTO is essential for stress-induced cardiac hypertrophy, its underlying functional mechanisms in regulating maladaptive cardiac remodeling are not yet known.

Purpose
In this study, we showed the necessity of FTO dependent m6A methylation in coordinating the molecular and signaling events that are engaged in cardiac hypertrophy, and further identified the detrimental signaling mechanisms that are regulated by FTO during pathological remodeling.

Methods
Firstly, the control and FTO-cKO (cardiomyocyte specific FTO knockout) group mice were subjected to sham and TAC (transverse aortic constriction) operation. Echocardiography was performed 1 week post-TAC. Secondly, m6A RNA immunoprecipitation (meRIP) sequencing were performed from the isolated mice heart tissue. Additionally, the effect of apoptosis and mTORC1 upon FTO depletion were analysed in both rodents and iPS-CMs. In vitro the interrelation between FTO demethylase, mTORC1 and autophagy in the regulation of cardiac apoptosis were identified by 1. inhibiting mTORC1 pathway with specific inhibitors, and by 2. inhibiting 'late autophagy' in FTO silenced iPS-CMs.

Results
In contrast to control mice, which exhibit concentric hypertrophy at the beginning of induced pressure overload (PO), echo analysis of one week post-TAC revealed that FTOcKO mice develop a DCM-like phenotype. Further, MeRIP-seq data showed that there is deregulation in the m6A methylation with FTO depletion. Around 114 differently hypermethylated transcripts and 58 differentially hypomethylated transcripts were discovered in FTOcKO sham as compared to Control sham; these transcripts are involved in the control of apoptosis, the mTORC1 signaling pathway, lysosomal biogenesis, and autophagy. In both rodents and iPS-CMs, FTO ablation dramatically enhances cardiac apoptosis and the mTORC1 signaling pathway. Furthermore, inhibition of mTORC1 pathway attenuates cardiac apoptosis in siFTO-iPS-CMs. Moreover, autophagic flux analysis revealed that FTO depletion cause autophagic flux impairment and exacerbate cardiac apoptosis. However, the autophagic flux is ameliorated with mTORC1 inhibition in late-autophagy inhibited siFTO-iPS-CMs.

Conclusion
Our data unravel the novel roles of FTO demethylase in the course of cardiac remodeling, which opens doors to therapeutic interventions in the treatment of cardiac hypertrophy and heart failure.
Melanocortin 1 receptor deficiency protects against pathological cardiac hypertrophy
Authors: Suominen A , Ruohonen S , Szabo Z , Savontaus E , Kerkela R , Rinne P 
Published: November 2023

Abstract

Background
The melanocortin system, including adrenocorticotropic hormone, melanocyte-stimulating hormones and five melanocortin receptors (MC-R), regulates important physiological functions such as pigmentation and energy homeostasis. It has been also recently implicated in the regulation of pathological cardiac remodeling but the role of different MC-R subtypes in the heart remain unknown.

Purpose
Based on the abundant cardiac expression of MC1-R, we hypothesized that it is functionally active in the heart and regulates pathological cardiac remodeling.

Methods
Rat H9c2 cells were used to study the effects of the selective MC1-R agonist LD211 on intracellular signaling cascades, gene expression and cellular growth response by using Western blotting, quantitative RT-PCR and 3H-leucine incorporation assay, respectively. Recessive yellow mice (Mc1re/e) were used as a model of global MC1-R deficiency. Inducible cardiomyocyte-specific MC1-R knockout mouse model (Mc1r-cKO) was engineered by intercrossing MC1-R floxed mice (Mc1rfl/fl) with tamoxifen-inducible Myh6-MerCreMer transgenic mice (Myh6-MCM). Mc1re/e and Mc1r-cKO mice were subjected to transverse aortic constriction (TAC, 8 wks) or subcutaneous infusion of angiotensin II (Ang II, 4 wks) to induce pathological cardiac hypertrophy. Cardiac structure and function were measured by echocardiography and by histological examination of H&E-stained heart sections.

Results
Treatment of H9c2 cells with LD211 increased MAP-kinase p-38 phosphorylation (+53 %, P=0.005 vs control), upregulated the expression of B-type natriuretic peptide (Nppb, +40 %, P=0.03 vs control) and increased 3H-leucine incorporation (+27 %, P=0.006 vs control). Mc1re/e mice showed reduction in ventricular weight (-29 mg, P=0.03) compared to WT mice after TAC operation, and reduced left ventricular (LV) expression of atrial natriuretic peptide (Nppa) and fibrosis-related genes (Ctgf and Mmp2). In terms of LV systolic performance, TAC-operated Mc1re/e mice showed tendency towards improved LV ejection fraction (EF, +6 %, P=0.06) compared to WT mice. To further investigate whether the phenotype of Mc1re/e mice is driven by deficient MC1-R signaling in cardiomyocytes, we characterized Mc1r-cKO mice, which recapitulated the phenotypic features of Mc1re/e mice. Specifically, TAC-operated Mc1r-cKO mice displayed reduced ventricular weight (-38 mg, P=0.007) and downregulation of LV expression of Nppa and fibrosis-related genes compared to Myh6-MCM mice. Likewise, in a model of Ang II-induced cardiac hypertrophy, Mc1r-cKO mice showed reduced ventricular weight (-10 mg, P=0.015) compared to Myh6-MCM mice, indicating that the protection against pathological cardiac hypertrophy was model-independent.

Conclusion
Our studies demonstrate that MC1-R activation promotes cardiomyocyte growth in vitro, while global and cardiomyocyte-specific MC1-R deficiency protects against pathological cardiac hypertrophy induced by TAC or Ang II infusion.
Thrombosis in the coronary microvasculature may be responsible for impaired cardiac relaxation and diastolic dysfunction
Authors: Rouault P , Guimbal S , Cornuault L , Foussard N , Bourguignon C , Grouthier V , Choveau F , Benoist D , Gadeau A P , Couffinhal T , Renault M A 
Published: November 2023

Abstract

Introduction
Heart Failure with Preserved Ejection Fraction (HFpEF) is proposed to be caused by endothelial dysfunction in cardiac small vessels. We previously identified Hhipl1,as a gene upregulated in the coronary vasculature of Leptin receptor deficient mice (Leprdb/db) a well-established mouse model of HFpEF. Importantly, Hhipl1 encodes for a decoy receptor of Desert Hedgehog (DHH) which is known to be critical for endothelial integrity.

Objective
Our objective is to investigate the functional consequences of impaired Hedgehog (HH) signaling in the adult heart in order to identify novel mechanisms underlying the development of diastolic dysfunction.

Method
To do so, Cdh5-Cre/ERT2, DhhFlox/Flox (DhhECKO) mice and their control littermates were administered with tamoxifen at 8 weeks of age to induce Dhh KO. Their cardiac function, exercise tolerance, and the phenotype of their coronary vasculature were assessed one month later.

Results
DhhECKO mice presented significantly reduced exercise tolerance, increased end diastolic pressure (EDP) and Tau, with no change in their ejection fraction consistent with diastolic dysfunction. At molecular and cellular level, impaired cardiac relaxation in DhhECKO mice was associated with a significantly decreased phospholamban phosphorylation on Thr17 and an alteration of sarcomeric shortening in ex-vivo. Besides, as expected, DhhECKO mice exhibited phenotypic changes in their coronary vasculature including a prominent pro-thrombotic phenotype (63±6,2 vs 25±5,2 thrombi/mm²; p&lt;0,001) leading to an impaired capillary perfusion and local hypoxia. Notably, antiaggregant therapies (aspirin and clopidogrel) prevented the occurrence of both diastolic dysfunction and exercise intolerance in DhhECKO mice demonstrating for the first time that thrombosis may promote diastolic dysfunction. Importantly, we confirmed the critical role of thrombosis in Leprdb/db mice which also displayed increased cardiac small vessel thrombosis in comparison to control mice. Alike DhhECKO mice, we found that antiaggregants decreased EDP (6,3±0,4 mmHg in aspirin-treated vs 11,3 ± 0,79 in control mice; p=0,001) and improved exercise tolerance in Leprdb/db mice (34 ± 2,52 min in aspirin-treated vs 24 ± 3,55 in control mice; p=0,004).

Conclusion
Altogether, these results demonstrate that small vessel thrombosis may participate in the pathophysiology of heart failure with preserved ejection fraction.