Rattus norvegicus
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ABSTRACT:
PROVIDER: PRJNA134039 | ENA |
REPOSITORIES: ENA
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Project description:Ischemia, fibrosis, and remodeling lead to heart failure after severe myocardial infarction (MI). Myoblast sheet transplantation is a promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in this detrimental disease. We hypothesized that in a rat model of MI-induced chronic heart failure this therapy could further be improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression using microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for four weeks. Thereafter, we administered L6-WT (n=15) or L6-HGF (n=16) myoblast sheet therapy. Control rats (n=13) underwent LAD ligation and rethoracotomy without therapy and five rats underwent sham-operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy administration. We analyzed cardiac angiogenesis and left ventricular architecture from histological sections 4 weeks after therapy. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF-expression. Analysis of the L6 rat skeletal myoblast cell line and myoblast cell sheets with constitutive human HGF expression.
2010-12-10 | E-GEOD-25752 | biostudies-arrayexpress
Project description:Ischemia, fibrosis, and remodeling lead to heart failure after severe myocardial infarction (MI). Myoblast sheet transplantation is a promising therapy to enhance cardiac function and induce therapeutic angiogenesis via a paracrine mechanism in this detrimental disease. We hypothesized that in a rat model of MI-induced chronic heart failure this therapy could further be improved by overexpression of the antiapoptotic, antifibrotic, and proangiogenic hepatocyte growth factor (HGF) in the myoblast sheets. We studied the ability of wild type (L6-WT) and human HGF-expressing (L6-HGF) L6 myoblast sheet-derived paracrine factors to stimulate cardiomyocyte, endothelial cell, or smooth muscle cell migration in culture. Further, we studied the autocrine effect of hHGF-expression on myoblast gene expression using microarray analysis. We induced MI in Wistar rats by left anterior descending coronary artery (LAD) ligation and allowed heart failure to develop for four weeks. Thereafter, we administered L6-WT (n=15) or L6-HGF (n=16) myoblast sheet therapy. Control rats (n=13) underwent LAD ligation and rethoracotomy without therapy and five rats underwent sham-operation in both surgeries. We evaluated cardiac function with echocardiography at 2 and 4 weeks after therapy administration. We analyzed cardiac angiogenesis and left ventricular architecture from histological sections 4 weeks after therapy. Paracrine mediators from L6-HGF myoblast sheets effectively induced migration of cardiac endothelial and smooth muscle cells but not cardiomyocytes. Microarray data revealed that hHGF-expression modulated myoblast gene expression. In vivo, L6-HGF sheet therapy effectively stimulated angiogenesis in the infarcted and non-infarcted areas. Both L6-WT and L6-HGF therapies enhanced cardiac function and inhibited remodeling in a similar fashion. In conclusion, L6-HGF therapy effectively induced angiogenesis in the chronically failing heart. Cardiac function, however, was not further enhanced by hHGF-expression.
2010-12-10 | GSE25752 | GEO
Project description:Proteomic analysis of the changes in kidney upon chronic heart failure in a rat model. Heart failure develops due to surgically created aorto-venoufistula.
2018-09-24 | PXD009296 | Pride
Project description:Despite continued progress, therapies to augment contractile function and prevent arrhythmias in patients with heart disease remain limited. Here, we present a two-pronged gene therapy approach whereby simultaneous augmentation of peak Na+ current and Ca2+ transient amplitude in cardiomyocytes (CMs) effectively alleviates pathogenesis of heart failure. Specifically, using in vitro engineered tissue models of neonatal rat CMs, ex vivo adult mouse CMs, and in silico rabbit CMs, we show that expression of prokaryotic Na+ channels (BacNav) dose-dependently enhances Ca2+ transient amplitude and contractility of CMs by modulating the activity of the Na+/Ca2+ exchanger and increasing sarcoplasmic reticulum Ca2+ stores. In vivo, AAV9-mediated BacNav therapy rescues contractile deficit and prevents arrhythmias in a pressure-overload induced model of chronic heart failure in mice. BacNav therapy also confers protective effects on pressure-overload induced dysregulation of the cardiac transcriptome. We further establish the safety of long-term systemic delivery of AAV9-BacNav in mice. Collectively, these studies support the translational promise of BacNav gene delivery as a novel therapy for electrical and contractile dysfunction in heart failure.
2026-03-11 | GSE306122 | GEO
Project description:The molecular mechanisms of progressive right heart failure are incompletely understood. We systematically examined transcriptomic changes occurring over months in isolated cardiomyocytes or whole heart tissues from failing right and left ventricles in rat models of pulmonary artery (PAB) or aortic banding (AOB). Detailed bioinformatics analyses resulted in the identification of gene signatures, protein, and transcription factor networks specific to ventricles and compensated or decompensated disease states. Proteomic and RNA-FISH analyses confirmed PAB-mediated regulation of key genes (including proenkephalin) and revealed spatially heterogeneous mRNA expression in the heart. Intersection of rat PAB-specific gene sets with transcriptome data sets from human patients with chronic thromboembolic pulmonary hypertension led to the identification of more than 50 genes whose expression levels correlated with the severity of right heart disease, including multiple matrix-regulating and secreted factors. These data define a conserved, differentially regulated genetic network associated with right heart failure in rats and humans
2024-04-11 | PXD047022 | Pride
Project description:Coronary microvascular dysfunction combined with maladaptive cardiomyocyte morphology and energetics are major contributors towards heart failure advancement. Thus dually enhancing cardiac angiogenesis and targeting cardiomyocyte function to slow, or reverse, the development of heart failure is a logical step towards improved therapy. We present evidence for the potential to repurpose a former anti-cancer Arg-Gly-Asp (RGD)-mimetic pentapeptide, Cilengitide, here used at low doses. Cilengitide targets avb3 integrin and this integrin is upregulated in human dilated and ischemic cardiomyopathies. Treatment of mice after transverse aortic constriction (TAC) surgery with low dose Cilengitide (ldCil) enhances coronary angiogenesis and directly affects cardiomyocyte hypertrophy with a correlating reduction disease severity. At a molecular level ldCil treatment has a direct effect on cardiac endothelial cell transcriptomic profiles with a significant enhancement of proangiogenic signalling pathways, corroborating the enhanced angiogenic phenotype after ldCil treatment.
2019-08-23 | GSE127854 | GEO
Project description:Baroreflex control of cardiac contraction (positive inotropy) through sympathetic nerve activation is important to maintain cardiocirculatory homeostasis. Transient receptor potential canonical subfamily (TRPC) channels are responsible for alfa1-adrenoceptor (alfa1AR)-stimulated cation entry and their upregulation is reportedly associated with pathological cardiac remodeling, but whether TRPC channels participate in physiological pump functions remains unclear. Here, we demonstrate that TRPC6-specific Zn2+ influx potentiates alfa-adrenoceptor (alfaAR)-stimulated positive inotropy in rodent cardiomyocytes. Deletion of the trpc6 gene impairs sympathetic nerve-activated positive inotropy, but not chronotropy in mice. TRPC6-mediated Zn2+ influx boosts alfa1AR-stimulatedalfaAR/Gs-dependent signaling in rat cardiomyocytes by inhibiting alfa-arrestin-mediated alfaAR internalization. Replacing two TRPC6-specific amino acids in the pore region with those of TRPC3 diminishes the alfa1AR-stimulated Zn2+ influx and positive inotropic response. Pharmacological enhancement of TRPC6-mediated Zn2+ influx prevents the progression of heart failure in dilated cardiomyopathy mice. Our data provide evidence that TRPC6-mediated Zn2+ influx with α1AR stimulation enhances baroreflex-induced positive inotropy, which may be a new therapeutic strategy for chronic heart failure.
2022-09-14 | GSE189494 | GEO
Project description:Pulmonary hypertension is a frequent consequence of left heart disease and congestive heart failure (CHF) and causes extensive lung vascular remodelling which leads to right ventricular failure. Functional genomics underlying this structural remodelling are unknown but present potential targets for novel therapeutic strategies. We used microarrays to detail the gene expression underlying vascular remodeling in the pathogenesis of pulmonary hypertension and identified distinct classes of up-regulated genes during this process. Control rat lung samples were compared to samples of aortic banding rat lungs which exhibit pulmonary hypertension
2009-06-16 | E-GEOD-16624 | biostudies-arrayexpress
Project description:Diabetic cardiomyopathy (DCM) is one of the major causes of heart failure in diabetic patients, but its pathogenesis remains unclear. Sodium glucose cotransporter 2 inhibitors (SGLT2i) can effectively reduce the risk of cardiovascular death and heart failure in DCM patients, but the underlying mechanism has not been elucidated. We established a DCM rat model followed by treatment with empagliflozin (EMPA) for 12 weeks. The proteomics of the myocardium in the rat model was performed to identify the potential targets and signaling pathways associated with the cardiovascular benefit of SGLT2i.
2023-03-10 | PXD036090 | Pride
Project description:Summary: Heart failure is frequently accompanied by pleural effusion, yet the biological impact of heart failure–associated pleural fluid on vascular endothelial function remains unclear. Here, we show that heart failure pleural fluid impairs endothelial barrier integrity and angiogenic capacity in human umbilical vein endothelial cells. Functional assays revealed increased permeability, reduced migration, and altered tube formation following treatment with patient-derived pleural fluid. Mechanistically, heart failure pleural fluid increased reactive oxygen species production and inflammatory signaling while downregulating tight junction protein ZO-1. Small RNA profiling identified miR 501 3p as a key mediator of these effects. Gain- and loss-of-function experiments demonstrated that miR 501 3p directly regulates ZO-1 expression and contributes to barrier disruption. These findings establish a microRNA-dependent mechanism linking heart failure pleural fluid to endothelial dysfunction and suggest a potential molecular pathway contributing to vascular complications in heart failure.
2026-03-12 | GSE319996 | GEO