Direct in vivo cardiac reprogramming improves cardiac function and ventricular remodeling in chronic MI.
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ABSTRACT:
PROVIDER: PRJNA1003121 | ENA |
REPOSITORIES: ENA
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Project description:Heart failure (HF) is a leading cause of morbidity and mortality. As adult cardiomyocytes (CMs) have little regenerative capacity, after myocardial infarction (MI), resident cardiac fibroblasts (CFs) synthesize extracellular matrix to form scar tissues, resulting in myocardial remodeling and HF. Thus, both cardiac regeneration and fibrosis are therapeutic targets for chronic MI. We previously reported that fibroblasts were directly reprogrammed into induced CMs (iCMs) by overexpression of cardiogenic transcription factors in acute and chronic MI. Here we show that in vivo cardiac reprogramming improved cardiac function, and reversed cardiac remodeling in chronic MI using a novel transgenic mouse system. Transcriptome analysis revealed that in vivo cardiac reprogramming suppressed signs of fibrosis and inflammation. Thus, in vivo cardiac reprogramming may be a promising approach for chronic HF.
2024-07-01 | GSE240310 | GEO
Project description:Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction (MI). Accumulating data show that ischemia, sympathetic activation, and inflammation contribute to arrhythmogenesis. However, the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remain undefined. We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in MI. Concomitant with increased ventricular pressure, Piezo1, as a newly recognized mechano-sensitive cation channel, was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure. Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes, which are responsible for intracellular calcium homeostasis and intercellular communication. Cardiomyocyte-conditional Piezo1 knockout mice (Piezo1Cko) exhibited preserved cardiac function after MI. Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI with a markedly reduced incidence of ventricular tachycardia. In contrast, activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment. Mechanistically, Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca2+overload and increasing the activation of Ca2+-modulated signaling, CaMKII, and calpain, which led to the enhancement of phosphorylation of RyR2 and further increment of Ca2+leaking, finally provoking cardiac arrhythmias. Furthermore, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential, inducing early afterdepolarization, and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling, which is achieved by regulating Ca2+handling, implying a promising therapeutic target in sudden cardiac death and heart failure.
2025-04-30 | GSE230042 | GEO
Project description:Neuregulin-1 (NRG-1) is a paracrine factor critical for cardiac development. We have been examining whether the recombinant NRG-1β isoform known as glial growth factor 2 (GGF2) has therapeutic potential for heart failure. In both small and large animals after experimental myocardial infarction (MI) we have found that GGF2 treatment improves myocardial function and limits progressive myocardial remodeling. To understand potential mechanisms for this effect, we compared gene expression in swine by microarray analysis. We used microarrays to compared th the global gene expression underlying the efficacy of GGF2 treatment for heart injury. Left ventricular tissue remote from the site of infarct was collected from each of 8 animals (3 untreated controls, 3 low dose GGF2-treated and 2 high dose GGF2-treated) and processed for gene expression microarray analysis using Affymetrix porcine genome GeneChips.
2014-06-21 | E-GEOD-48255 | biostudies-arrayexpress
Project description:Cardiac fibroblasts stay relatively quiescent under normal condition. These cells differentiate to myofibroblasts after myocardial infarction (MI), characterized by the expression of contractile proteins and secretion of elevated levels of extracellular matrix proteins, leading to cardiac remodeling. The differentiated myofiroblasts gradually lose most myofibroblast phenotypes but still persist in the infarct area to maintain the tissue structural integrity. We used microarrays to reveal the change in cardiac fibroblast gene expression profile after MI.
2018-02-24 | GSE111059 | GEO
Project description:In this study, we used a cardiac-specific, inducible expression system to activate YAP in adult mouse heart. Activation of YAP in adult heart promoted cardiomyocyte proliferation and did not deleteriously affect heart function. Furthermore, YAP activation after myocardial infarction (MI) preserved heart function and reduced infarct size. Using adeno-associated virus subtype 9 (AAV9) as a delivery vector, we expressed human YAP in the murine myocardium immediately after MI. We found that AAV9:hYAP significantly improved cardiac function and mouse survival. AAV9:hYAP did not exert its salutary effects by reducing cardiomyocyte apoptosis. Rather, we found that AAV9:hYAP stimulated adult cardiomyocyte proliferation. Gene expression profiling indicated that AAV9:hYAP stimulated cell cycle gene expression, enhanced TGFβ-signaling, and activated of components of the inflammatory response.Cardiac specific YAP activation after MI mitigated myocardial injury after MI, improved cardiac function and mouse survival. These findings suggest that therapeutic activation of hYAP or its downstream targets, potentially through AAV-mediated gene therapy, may be a strategy to improve outcome after MI. Three groups were involved in this study: sham group, AAV9:Luci+MI group and AAV9-YAP+MI group. Each group contained three biological replicates. The sham group had neither myocardial infarction nor AAV injection. The AAV9:Luci +MI(L for brief) group had myocardial infarction and injected with AAV9:Luic. The AAV9:hYAP+MI(YAP for brief) group had myocardial infarction and injected with AAV9:hYAP. 5 days after MI and AAV injection, the heart apexes were collected and the total RNA were isolated for microarray analysis.
2014-05-26 | E-GEOD-54612 | biostudies-arrayexpress
Project description:Direct cardiac reprogramming of fibroblast to cardiomyocytes represents a potential means of restoring cardiac function following injury. However, aged and adult fibroblast are less efficient for reprogramming compared with neonatal fibroblast. In this study, through the joint analysis of RNAseq and ATACseq, we found that compared with Neo-iCM, cardiac related features were down-regulated with aging, while fibrosis and SASP related genes were significantly up-regulated with aging. Single-cell transcriptomics reveals a bifurcated trajectory of aged iCM reprogramming. Then, we screened 51 transcriptomic and epigenomic regulators of the barriers to aged-iCM reprogramming and found that Nuclear receptor subfamily 4 group A member 3 (Nr4a3), an pro-inflammatory transcription factor, induced cellular senescence to inhibit direct reprogramming during aging. Mechanistically, knockdown of Nr4a3 enhanced direct cardiac reprogramming by promoting cardiac gene programs and inhibiting fibrosis pathway and secretes SASP. In addition, knockdown of Nr4a3 promoted human reprogramming in primary ventricular human cardiac fibroblasts (HCFs) and improved heart function after MI.
2025-08-22 | GSE267450 | GEO
Project description:Direct cardiac reprogramming of fibroblast to cardiomyocytes represents a potential means of restoring cardiac function following injury. However, aged and adult fibroblast are less efficient for reprogramming compared with neonatal fibroblast. In this study, through the joint analysis of RNAseq and ATACseq, we found that compared with Neo-iCM, cardiac related features were down-regulated with aging, while fibrosis and SASP related genes were significantly up-regulated with aging. Single-cell transcriptomics reveals a bifurcated trajectory of aged iCM reprogramming. Then, we screened 51 transcriptomic and epigenomic regulators of the barriers to aged-iCM reprogramming and found that Nuclear receptor subfamily 4 group A member 3 (Nr4a3), an pro-inflammatory transcription factor, induced cellular senescence to inhibit direct reprogramming during aging. Mechanistically, knockdown of Nr4a3 enhanced direct cardiac reprogramming by promoting cardiac gene programs and inhibiting fibrosis pathway and secretes SASP. In addition, knockdown of Nr4a3 promoted human reprogramming in primary ventricular human cardiac fibroblasts (HCFs) and improved heart function after MI.
2025-08-22 | GSE267448 | GEO
Project description:Direct cardiac reprogramming of fibroblast to cardiomyocytes represents a potential means of restoring cardiac function following injury. However, aged and adult fibroblast are less efficient for reprogramming compared with neonatal fibroblast. In this study, through the joint analysis of RNAseq and ATACseq, we found that compared with Neo-iCM, cardiac related features were down-regulated with aging, while fibrosis and SASP related genes were significantly up-regulated with aging. Single-cell transcriptomics reveals a bifurcated trajectory of aged iCM reprogramming. Then, we screened 51 transcriptomic and epigenomic regulators of the barriers to aged-iCM reprogramming and found that Nuclear receptor subfamily 4 group A member 3 (Nr4a3), an pro-inflammatory transcription factor, induced cellular senescence to inhibit direct reprogramming during aging. Mechanistically, knockdown of Nr4a3 enhanced direct cardiac reprogramming by promoting cardiac gene programs and inhibiting fibrosis pathway and secretes SASP. In addition, knockdown of Nr4a3 promoted human reprogramming in primary ventricular human cardiac fibroblasts (HCFs) and improved heart function after MI.
2025-08-22 | GSE267447 | GEO
Project description:Untreated Rat Cardiac Ventricular tissue Age
| PRJNA1139213 | ENA
Project description:Thyroid hormone improves left ventricular remodeling and cardiac performance after myocardial infarction (MI), but the molecular basis is unknown. This study was designed to detect gene expression changes in left ventricular non-infarcted areas at 4 weeks following myocardial infarction with and without thyroid hormone treatment. The results suggest that altered expression of genes for molecular function and biological process may be involved in the beneficial effects of thyroid hormone treatment following myocardial infarction in rats. MI was produced by ligation of the left anterior descending coronary artery in female SD rats. Rats were divided into the following groups: (1) Sham MI, (2) MI, and (3) MI+T4 treatment (T4 pellet 3.3mg, 60 days release, implanted subcutaneously immediately following MI). Four weeks after surgery, total RNA was isolated from left ventricular non-infarcted areas for microarray analysis using the Illumina RatRef-12 Expression BeadChip Platform.
2012-04-30 | E-GEOD-35088 | biostudies-arrayexpress