tbuckley/cabot-search huggingface dataset:
Meteorin-like regulates cardiac hypertrophy and associated metabolic plasticity during gestation and lactation
Authors: A Blasco-Roset, C Ruperez, E Cerrato, F Villarroya, T Quesada-Lopez, A Planavila
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministerio de investigación y ciencia de España Introduction Pregnancy-induced cardiac hypertrophy is considered a physiological, reversible process (1, 2). However, cardiac remodeling after delivery and through lactation, as well as mechanisms driving hypertrophy reversion, remain undefined. In recent studies, we described the cardioprotective role of Meteorin-like (Metrnl) during pathological remodeling of the myocardium (3). Its role during gestation and lactation in the maternal heart is completely unknown. Purpose To characterize pregnancy-induced cardiac hypertrophy and its underlying mechanisms, and to determine the role of Metrnl in the cardiac remodeling associated to pregnancy and lactation. Methods C57BL/6J wild-type (WT) and Metrnl knockout (Metrnl-KO) female mice were studied during gestation, lactation and weaning. Echocardiographic measurements and cardiac samples were obtained from virgin control animals (V), pregnant mice at term (E18), lactating females at days 14 and 21 (L14 and L21), and mice 7 and 21 days after L21 weaning (W7 and W21). Results In WT females, pregnancy induces eccentric cardiac hypertrophy characterized by a major dilation of the left ventricle, a phenomenon that is maintained and further increased during lactation, reaching the highest degree of eccentric hypertrophy by L14. After weaning, hypertrophy is totally reversed (Figure 1A). By contrast, Metrnl-KO mice show a more pathological cardiac phenotype characterised by an exacerbated eccentric hypertrophy development accompanied by reduced ejection fraction. Post-weaning resolution is also delayed compared to WT. Next, we analysed cardiac metabolism since during the latest stages of gestation, the heart relies more on fatty acid utilization due to the increased glucose demands of the foetus (Figure 1B). We found that in WT mice, cardiac expression of genes linked to fatty acid oxidation (FAO; Acadm, Pdk4 and Cpt1b) is increased during gestation and repressed during lactation in parallel with cardiac Metrnl expression, recovering basal levels by W7. By contrast, in Metrnl-KO mice mitochondrial pyruvate transporter Mpc1 expression is increased during the whole process, while Pdk4 and Cpt1b protein levels are lower, suggesting a reliance of these hearts on glucose metabolism during pregnancy and post-partum. Conclusions The maternal heart develops an adaptive pregnancy-induced cardiac hypertrophy, a condition that initiates at gestation, peaks by day 14 of lactation and starts reverting upon weaning. Metrnl is necessary for the correct development of cardiac adaptations associated with pregnancy/lactation.Figure 1
Liraglutide prevents hyperglycemia-induced senescence and proinflammatory monocyte differentiation in CD34+ hematopoietic stem cells
Authors: G Damiano, R Rinaldi, G Pompilio, M C Vinci
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Italian Ministry of Health- Ricerca Finalizzata Background Diabetes mellitus (DM) is known to promote aberrant activation of immune cells that contribute to the onset and progression of chronic inflammation and atherosclerosis in DM patients (1). This phenomenon, termed 'trained immunity', appears to be initiated in hematopoietic stem/progenitor cells (HSPCs). In recent years, there has been great interest in investigating the pleiotropic effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs), including anti-inflammatory and immunological properties. We have recently demonstrated that HSPCs express the GLP-1R whose stimulation with the agonist liraglutide (LIRA) prevents oxidative stress and functional impairment induced by hyperglycemic conditions (HG) (2). On this basis, we hypothesized that LIRA treatment can also avert HG-induced senescence and proinflammatory myeloid differentiation of HSPCs. Purpose To evaluate senescence and inflammatory myeloid differentiation of CD34+ HSPCs after HG exposure in the presence or not of GLP1R agonist. Methods CD34+ HSPCs derived from cord blood of healthy donors were expanded in normal-glucose (NG; with 30 mM mannitol for osmotic control) or high-glucose (HG; 30 mM) and treated or not with LIRA (100nM) in serum-free medium plus cytokines (FLT3, SCF, IL3 and IL6) for up to 20 days. The expression of p21, p27, IL6, TNFα, and NFkB-p65 genes was assessed by qPCR. ROS production and CD34+ HSPC-derived monocyte subsets were evaluated by flow cytometry whereas cytokine secretion after LPS stimulation was measured by ELISA assay. Results LIRA treatment showed to significantly prevent the impairment of CD34+ HSPC proliferation as well as the upregulation of senescence-associated secretory phenotype (SASP) genes such as p21, p27, NFkB-p65, IL6, and TNFα in HG-CD34+ HSPCs when compared to HG cell alone (one-way ANOVA; p≤0.05). Interestingly, these pharmacological effects were associated with a significant reduction in HG-induced ROS production. Myeloid differentiation in vitro of HG-CD34+ HSPCs generated monocytes composed mainly of an inflammatory and highly reactive intermediate (CD14++CD16+) subpopulation characterized by higher LPS-induced release of IL6 and TNFα. LIRA treatment significantly prevented both the accumulation of intermediate (CD14++CD16+) monocyte subpopulation from differentiating HG-CD34+ HSPCs and their inflammatory phenotype (one-way ANOVA; p≤0.05). Conclusions These results demonstrate that HG exposure alters the differentiation program of CD34+ HSPCs towards more inflammatory immune cell components and suggest that GLP1R agonists are endowed with immunomodulatory properties that could be further developed and exploited for the treatment of immune system dysregulation in diabetes.
Targeting serotonin receptor 7 to improve survival after myocardial infarction
Authors: F Mueller, S Erschow, F S Bahr, N Benen, E Ponimaskin, M Ricke-Hoch
Journal: Cardiovascular Research (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.
Exploring the interactions between cardiomyocytes and endothelial cells to induce cardiac revascularization and regeneration
Authors: R Vuerich, A Colliva, S Vodret, M C Volpe, L Braga, G Canarutto, S Piazza, T Pedrazzini, M Chiesa, M Cauteruccio, M Ramadan, L Zentilin, M Giacca, S Zacchigna
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements None. Background The adult heart is unable to regenerate after ischemic injury, primarily due to the incapacity of cardiomyocyte (CM) to re-enter in the cell cycle and endothelial cells (EC) to form new vessels. Interestingly, our recent data have unveiled that the decline of CM proliferation after birth is paralleled by a reduction in angiogenic potential. Nevertheless, the precise mechanisms governing angiogenesis inhibition in the adult heart remain elusive. We hypothesize that the terminal differentiation of CMs after birth leads to the paracrine suppression of EC proliferation. Purpose This study aims to identify membrane or secreted factors produced by adult CMs that inhibit EC proliferation and vessel formation in order to create new therapeutic strategies to induce cardiac revascularization and regeneration. Material and Methods To validate our hypothesis, ECs were co-cultured with CMs at distinct differentiation stages. Leveraging existing RNA sequencing datasets, we generated an interactome between ligands produced by CMs and receptors expressed by cardiac ECs. Through gain and loss of function studies, we identified pivotal anti-angiogenic factors and subsequently knocked-out the corresponding genes in Cas9 mice, with the aim of rescue the angiogenic potential of the adult heart. Concurrently, we assessed the ability of miR199a, a pro-proliferative miRNA known for inducing CM de-differentiation, to elicit EC proliferation and angiogenesis when delivered to the adult heart together with VEGF-A, utilizing adeno-associated viral vectors. Results Our findings revealed that adult CMs impaired EC proliferation. Comprehensive analysis identified 20 membrane and secreted factors, establishing 118 ligand-receptor interactions between CMs and ECs. Notably, KCNJ11 and CD74 emerged as key factors, as validated through gain and loss of function experiments. In vivo knockout of these genes in CMs led to significant increase in EC proliferation and the formation of neo-vessels. Furthermore, CM de-differentiation induced by miR199a demonstrated the capacity to promote EC proliferation and neo-vessel formation upon VEGF-A stimulation. Conclusions Collectively, this work demonstrated that fully mature CMs have a role in limiting angiogenic potential of the adult heart, likely explaining the failure of therapeutic angiogenesis approaches attempted so far. Our results suggest that innovative strategies targeting CM-EC cross-talk or inducing partial CM de-differentiation may open new therapeutic avenues in the field of cardiac regeneration.Adult CMs inhibit EC proliferationCMdedifferentiation rescues angiogenesis
Zebrafish dspb-/- mutant as model for arrhythmogenic cardiomyopathy - impact of physical activity
Authors: S Munteanu, J Wagih Gomez, E M Nicolas Rocamora, C Gil Ortuno, A Bernabe Garcia, A Judez Serrano, C Martinez Perez, J R Gimeno Blanes, M L Cayuela Fuentes, M Sabater Molina
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Instituto de Salud Carlos III Background Zebrafish has been reported as a model to study the Arrythmogenic cardiomyopathy, which is generally associated with desmosomal gene mutations. We have identified a founder non-sense human variant in patients from our region (DSP p.Q447*) associated with left ventricle Arrythmogenic cardiomyopathy and we have selected it for modelling in zebra fish by CRISPR/Cas9 method, choosing exon 10 as the region of homology to be mutated and obtaining the p.T449fs* variant that determines a premature stop codon. Purpose Our aim was the characterization of dspb-/- mutants, studying the impact of physical activity in development of the disease. Methods The characterization of phenotype was performed through viability assays, cardiac function measurements and gene expression assays in larvae (3 days post fertilization) and adult (8 months old) individuals. The impact of physical activity was determined through moderated training periods (1 month) and endurance assays using a swimming tunnel. Results Viability assays showed that dspb mutants suffer a premature death, with significant higher mortality rates than the wildtype group (survival WT 89.7% vs dspb-/- 61.3%, p&amp;lt;0.01). Larvae cardiac function showed dspb mutants had a higher heart rate (WT 106.8 ± 26.8 vs dspb-/- 141.0 ± 7.2, p&amp;lt;0.01) while echocardiography showed differences in heart rate (WT 127.2 ± 49,8 vs dspb-/- 219.2 ± 26.8, p&amp;lt;0.05), systolic (WT 26.9 ± 5.3 vs dspb-/- 18.5 ± 5.2, p&amp;lt;0.05) and diastolic (WT 37.6 ± 8.4 vs dspb-/- 23.7 ± 5.4, p&amp;lt;0.05) areas. Gene expression analysis in adult heart showed dspb expression drastically decreased (WT 0.9 ± 0.1 vs dspb-/- 0.4 ± 0.01, p&amp;lt;0.01), whilst pkp2 expression increased (WT 0.9 ± 0.1 vs dspb-/- 2.59 ±0.22, p&amp;lt;0.001) as well as dspa gene expression (wt 0.9 ± 0.1 vs dspb-/- 4.41 ± 0.18, p&amp;lt; 0.001) as a compensation mechanism. Moderated long term physical activity had a positive impact in heart rate (dspb-/-pre 219.2 ± 26.8 vs dspb-/-post 138 ± 7.5, p&amp;lt;0.01) and diastolic area (dspb-/-pre 24 ± 5 vs dspb-/-post 32 ± 2.1, p&amp;lt;0.05). Adult mutants showed a better endurance showing improvement in immobile cumulative duration (dspb-/-pre 849.3 ± 29.3 vs dspb-/-post 179.8 ± 29.7, p&amp;lt;0.01) and immobile frequency (dspb-/-pre 5399.5 ± 1127.8 vs dspb-/-post 1310 ± 481.9, p&amp;lt;0.01). Conclusion The dspb-/- zebrafish presented pathological cardiac phenotype at larvae and adult stages, and less endurance in intensity exercises. The moderate exercise has turned out to be a beneficial modulator of the phenotype.
Propafenone-induced connexin-43 protein accumulation and intracellular dynamics
Authors: E Li, N Boujeddaine, B Mol, M A G Van Der Heyden
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): China Scholarship Council Background Connexin-43 (Cx43) plays a pivotal role in intercellular communication through gap junctions. It is instrumental in propagating electrical signals and allowing ions to flow between neighboring cardiomyocytes. This synchronized electrical activity allows the heart to work as a functional syncytium. Any disruption or malfunction of Cx43 can lead to arrhythmias and other cardiac issues. Understanding the functions and regulation of Cx43 is vital in both basic research and clinical contexts. Propafenone, a class Ic antiarrhythmic drug, has shown promise in rhythm control; however, its precise impact on cardiac cellular physiology, particularly regarding Cx43, remains incompletely understood. Purpose To investigate propafenone’s effect on Cx43 expression, physiology, and underlying mechanisms in cell systems. Methods Used cell lines include human embryonic kidney HEK293 cells transfected with Cx43; differentiated murine embryonic carcinoma EPI7 cells with an epithelioid morphology and visceral endoderm-like END2 cells, endogenously expressing high amounts of functional Cx43. Cx43 protein expression levels were determined by Western blot analysis, whereas immunofluorescence (IF) imaged by a Total Internal Reflection Fluorescence (TIRF) microscope was used to assess the subcellular localization of Cx43 proteins. Dye injections were used to gain insight into the effects of propafenone on Cx43 metabolic coupling. Results and Conclusion Full length Cx43 protein levels were increased after treatment with propafenone and IF microscopy showed an intracellular accumulation of Cx43 protein, both on ectopically and endogenously expressed Cx43. Propafenone did not alter Cx43 half-life, in contrast to the lysosomal inhibitor chloroquine. Finally, gap-junctional coupling was decreased by chronic propafenone treatment. We conclude that the class 1c antiarrhythmic drug propanone increases Cx43 protein expression, resulting in its intracellular accumulation, as a side effect.
Potential of [64Cu]Cu-RGD PET/CT for detection of cardiotoxicity in a rat model of doxorubicin induced heart failure
Authors: C Hoeeg, B Follin, C Grandjean, R Sejersten Ripa, A Ekblond, J Kastrup, T Binderup, A Kjaer
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the European Union’s Horizon 2020 research and innovation program (ERC Advanced Grant) and the Novo Nordisk Foundation. Background Doxorubicin is a common and highly effective chemotherapeutic. However, its use is limited by cardiotoxic side effects, which occur in 5-23 % of patients treated, and the lack of methods to detect these conditions at early time points. Purpose In the present study, we evaluated if [64Cu]Cu-RGD positron emission tomography/computed tomography (PET/CT) could detect cardiotoxicity in a rat model of doxorubicin induced heart failure. Methods Male Lewis rats were divided into two groups and treated with either a cumulative dose of 15 mg/kg doxorubicin (n = 15) or left untreated (n = 10). Cardiac anatomy and function were assessed using magnetic resonance imaging at baseline and in week eight. [64Cu]Cu-RGD PET/CT scans were performed in week four. All animal experiments were approved by the Danish Animal Experiments Inspectorate (authorization number 2016-15-0201-00920) and study performed in accordance with the ARRIVA guidelines. Results Doxorubicin treatment led to a decline in left ventricular ejection fraction (66.5 ± 0.85 % to 46.67 ± 0.84 %, p &amp;lt; 0.001), as well as an increase in septal and thymic uptake of [64Cu]Cu-RGD (0.46 ± 0.02 vs. 0.29 ± 0.04, &amp;lt;0.001 and 0.87 ± 0.03 vs. 0.40 ± 0.07, p &amp;lt; 0.001, respectively). In addition, doxorubicin altered the cardiac gene expression, led to infiltration of macrophages (0.90 ± 0.12 % vs. 0.30 ± 0.04 %, p &amp;lt;0.001), reduced endothelial content (0.19 ± 0.02 % vs. 0.47 ± 0.07 %, p &amp;lt; 0.001), and increased interstitial fibrosis (13.6 ± 0.86 % vs. 10.5 ± 0.66 %, p = 0.014). Furthermore, concentrations of inflammatory plasma proteins were increased in the doxorubicin group. Conclusion Doxorubicin treatment resulted in the development of cardiotoxicity and heart failure, which could be detected using [64Cu]Cu-RGD PET/CT at early time points. [64Cu]Cu-RGD uptake in the myocardial septum and thymus predicted low left ventricular ejection fraction in week eight, thus it may serve as an early marker of cardiotoxicity.Experimental setup and timeline
The role of FGL2 in vascular smooth muscle cell dysfunction in coronary artery bypass vein graft failure
Authors: M Jackson, A Bond, R Ascione, J Johnson, S J George
Journal: Cardiovascular Research (2024)

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): British Heart Foundation Rationale The sudden exposure of venous endothelial cells (vECs) to arterial fluid shear stress (FSS) is thought to be a major contributor to coronary artery bypass vein graft failure (VGF). However, the acute effects of arterial FSS on the vEC secretome and the corresponding effects on underlying vascular smooth muscle cells (VSMCs) remains poorly characterised. Methods &amp; Results Human umbilical vein endothelial cells (HUVECs; n=6) pre-conditioned to venous FSS (18h; 1.5 dynes/cm2) were further exposed to venous or arterial FSS (24h; 15 dynes/cm2) using an Ibidi pump system. Analysis of the EC secretome using Tandem Mass Tagging proteomics detected significantly increased fibroleukin (FGL2) in conditioned media from ECs exposed to arterial FSS compared to venous FSS (fold-change 1.97±0.72; P=0.0078). In addition, RT-qPCR analysis of FGL2 production showed a significant increase in vECs exposed to arterial FSS (2.11±0.27 vs. 0.05±0.04 log(copy number/mg); P=0.0312). Subsequently, pooled human saphenous vein VSMCs (3 donors per pool) were treated with conditioned media from ECs exposed to arterial FSS (n=6) which showed a significant increase in apoptosis, measured by active cleaved caspase-3 (CC3) immunocytochemistry (27±1% vs 22±1%; P=0.0391), and a significant decrease in the contractile markers smoothelin and desmin quantified by Western blotting (fold-change 0.76±0.06 and 0.44±0.11; P=0.004 and P=0.0421, respectively), in comparison to VSMCs treated with conditioned media from ECs exposed to venous FSS. Treatment of VSMCs (n=6) with recombinant FGL2 (20 ng/mL) for 72h likewise resulted in increased apoptosis (27±4% vs. 16±3%; P=0.0169) and decreased desmin and smoothelin (fold-change 0.68±0.03 and 0.61±0.07; P=0.0322 and P=0.0479, respectively). Conclusions The exposure of vECs to arterial FSS results in increased production and release of FGL2 which induced VSMC apoptosis and de-differentiation and therefore potentially contributes to VGF. Consequently, targeting FGL2 production or release may provide a therapeutic target to improve vein graft patency.