Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11
Published: Dec. 9, 2024
Heart failure is a complex syndrome characterized by impaired cardiac function. Despite improvements in treatment, the prevalence of heart continues to rise. The Cardiometabolic Index (CMI), novel measure combining abdominal obesity and lipid levels, has emerged as potential predictor metabolic risk.
Language: Английский
bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 9, 2024
Summary Cardiac maturation is an important developmental phase culminating in profound biological and functional changes to adapt the high demand environment after birth 1,2 . Maturation of human pluripotent stem cell-derived cardiac organoids (hCO) more closely resemble heart tissue critical for understanding disease pathology. Herein, we profile vivo 3 identify key signalling pathways that drive hCOs 4,5 Transient activation both 5’ AMP-activated kinase (AMPK) estrogen-related receptor (ERR) promoted hCO by mimicking increased demands post-natal development. cultured under these directed (DM) conditions (DM-hCOs) display robust transcriptional including expression mature sarcomeric oxidative phosphorylation genes resulting enhanced metabolic capacity. DM-hCOs have functionally properties such as sarcoplasmic reticulum-dependent calcium handling, accurate responses drug treatments perturbing excitation-coupling process ability detect ectopy CASQ2 RYR2 mutants. Importantly, DM- permit modelling complex processes desmoplakin ( DSP ) cardiomyopathy, which driven multiple cell types. Subsequently, deploy demonstrate bromodomain extra-terminal inhibitor INCB054329 rescues phenotype. Together, this study demonstrates recapitulating development promotes advanced enabling identification a therapeutic strategy DSP- cardiomyopathy.
Language: Английский
Citations
2
Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown
Published: April 10, 2024
Abstract The immaturity of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a major limitation for their use in drug screening to identify pro-arrhythmogenic or cardiotoxic molecules, thus hindering potential role guiding personalised selection patients. Here, we demonstrate an approach that combines lipid-enriched maturation medium, nanopatterning culture surfaces and electrostimulation generate iPSC-CMs with advanced electrophysiological, structural metabolic phenotype. Through systematic, stepwise parallel testing the three stimuli, emerged as pivotal factor enhance mitochondrial development improve electrophysiological properties iPSC-CMs. combined brought substantial modification current composition by increasing I Na , K1 Kr but decreasing Ca−L resulting significant change sensitivity cardioactive drugs. Transcriptome analysis revealed activation HMCES TFAM targets played development, whereas downregulation MAPK/PI3K signalling pathways SRF were associated polyploidy Taken together, our study provides mechanistic insights into more adult-like response.
Language: Английский
Citations
0
Theranostics, Journal Year: 2024, Volume and Issue: 14(11), P. 4462 - 4480
Published: Jan. 1, 2024
Rationale: Cardiomyocytes (CMs) undergo dramatic structural and functional changes in postnatal maturation; however, the regulatory mechanisms remain greatly unclear.Cypher/Z-band alternatively spliced PDZ-motif protein (ZASP) is an essential sarcomere component maintaining Z-disc stability.Deletion of mouse Cypher mutation human ZASP result dilated cardiomyopathy (DCM).Whether Cypher/ZASP participates CM maturation thereby affects cardiac function has not been answered.Methods: Immunofluorescence, transmission electron microscopy, real-time quantitative PCR, Western blot were utilized to identify role maturation.Subsequently, RNA sequencing bioinformatics analysis predicted serum response factor (SRF) as key regulator.Rescue experiments conducted using adenovirus or adeno-associated viruses encoding SRF, both vitro vivo.The molecular elucidated through G-actin/F-actin fractionation, nuclear-cytoplasmic extraction, actin disassembly assays, co-sedimentation assays.Results: deletion led impaired isoform switch morphological abnormalities mitochondria, transverse-tubules, intercalated discs.RNA-sequencing revealed significant dysregulation crucial genes related assembly, mitochondrial metabolism, electrophysiology absence Cypher.Furthermore, SRF was transcription mediating transcriptional differences.Subsequent rescue showed that re-expression during critical period effectively rectified defects notably improved Cypher-depleted mice.Mechanistically, deficiency resulted destabilization F-actin a notable increase G-actin levels, impeding nuclear localisation myocardin-related A (MRTFA) subsequently initiating transcription.Conclusion: plays actin-mediated MRTFA-SRF signalling.The linkage between late-onset DCM suggested, providing further insights into pathogenesis potential treatment strategies.
Language: Английский
Citations
0
Cellular Signalling, Journal Year: 2024, Volume and Issue: 124, P. 111397 - 111397
Published: Sept. 7, 2024
Language: Английский
Citations
0
Nature Cardiovascular Research, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 25, 2024
Language: Английский
Citations
0
Journal of Translational Medicine, Journal Year: 2024, Volume and Issue: 22(1)
Published: Nov. 28, 2024
Abstract Background Right ventricular volume overload (RVVO) is one of the most important hemodynamic characteristics in children with congenital heart disease (CHD) and failure, cardiomyocyte (CM) proliferation vital factors for improving cardiac performance. However, whether how RVVO reboots CM remains elusive. Methods results We first created a neonatal mouse model via abdominal aorta inferior vena cava-fistula microsurgery at postnatal day 7 (P7), edge window. subsequently performed bulk RNA-seq, single cell RNA-seq/flow cytometry, immunofluorescence staining on right ventricles (RV) mice P14/P21, defined as prepubertal stage, revealing that temporarily immune responses. Conclusions In considering importance proliferation, this study may bring an opportunity to create novel paradigm treat pediatric CHDs or failure. Graphical
Language: Английский
Citations
0
Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11
Published: Dec. 9, 2024
Heart failure is a complex syndrome characterized by impaired cardiac function. Despite improvements in treatment, the prevalence of heart continues to rise. The Cardiometabolic Index (CMI), novel measure combining abdominal obesity and lipid levels, has emerged as potential predictor metabolic risk.
Language: Английский
Citations
0