Connective Tissue Growth Factor Inhibition Enhances Cardiac Repair and Limits Fibrosis After Myocardial Infarction
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ABSTRACT:
PROVIDER: PRJNA530225 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8832260.fastq.gz | Fastqsanger.gz | |||
| SRR8832251.fastq.gz | Fastqsanger.gz | |||
| SRR8832261.fastq.gz | Fastqsanger.gz | |||
| SRR8832252.fastq.gz | Fastqsanger.gz | |||
| SRR8832262.fastq.gz | Fastqsanger.gz |
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Project description:Background. Accumulation of extracellular matrix in the myocardium attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Connective tissue growth factor (CTGF) is a matricellular protein that has been shown to promote development of cardiac fibrosis. Objectives. To investigate for the potential of CTGF monoclonal antibody (CTGF mAb) in protecting from development of cardiac fibrosis following myocardial infarction (MI), and to evaluate its effect during infarct repair and acute cardiac ischemia-reperfusion (I/R) injury. Methods. Mice were subjected to MI or to I/R injury and treated with either control IgG or CTGF mAb. Cultured human cardiac fibroblasts were used to investigate the signalling mechanisms modulated by CTGF mAb. Results. Treatment with CTGF mAb for four days from day three after MI improved survival, attenuated infarct expansion, and resulted in better preserved left ventricular (LV) systolic function. CTGF mAb therapy for six weeks from day seven after MI reduced the MI-induced increase in cardiomyocyte size, heart weight to body weight ratio and remote LV fibrosis. RNA sequencing analysis of LV samples showed that CTGF mAb induced expression of cardiac repair/developmental genes and normalized the MI-induced increase in expression of inflammatory/profibrotic genes. CTGF mAb induced c-Jun N-terminal kinase (JNK) phosphorylation in vivo and in vitro, and inhibition of JNK abrogated the reduced collagen production in CTGF mAb treated fibroblasts. Conclusions. Treatment with CTGF mAb induces expression of cardiac repair/developmental genes and inhibits expression of inflammatory/pro-fibrotic genes in MI hearts providing benefit during post-MI cardiac repair and reducing post-MI cardiac fibrosis.
2019-04-02 | GSE129134 | GEO
Project description:Myocardial infarction (MI)-induced cardiac fibrosis attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Expression of connective tissue growth factor (CTGF) is elevated in affected organs in virtually every fibrotic disorder and in the diseased human myocardium. Mice were subjected to treatment with a CTGF monoclonal antibody (mAb) during infarct repair, post-MI left ventricular (LV) remodeling, or acute ischemia-reperfusion injury. CTGF mAb therapy during infarct repair improved survival and reduced LV dysfunction, and reduced post-MI LV hypertrophy and fibrosis. Mechanistically, CTGF mAb therapy induced expression of cardiac developmental and/or repair genes and attenuated expression of inflammatory and/or fibrotic genes.
| S-EPMC6390503 | biostudies-literature
Project description:Tissue repair after myocardial infarction entails a vigorous angiogenic response that mitigates scarring and worsening of heart function and may represent a therapeutic target. Angiogenesis in the infarct wound is guided by incompletely defined myeloid cell–endothelial cell interactions. Here we identify the myeloid cell-expressed 75‑amino acid microprotein BRICK1 (short name: BRK1) as an indispensable driver of postinfarction angiogenesis. As a subunit of the intracellular actin-regulatory WAVE complex, BRK1 was not previously known to function outside the cell. We show that BRK1 translocates to the extracellular space after myocardial infarction in mice and humans. We find that BRK1 is not actively secreted but released from dying monocytes and macrophages. Cre-loxP-mediated myeloid cell-selective genetic deletion of Brk1 or antibody neutralization of extracellular BRK1 impaired microvessel formation in the infarct border zone and resulted in severe postinfarction heart failure in mice. Treatment with recombinant BRK1, conversely, preserved heart function after myocardial infarction. Mechanistically, BRK1 induced an angiogenic phenotype in human cardiac endothelial cells by signaling via the small GTPase RAP1 and mitogen-activated protein kinases 1 and 3 to promote retinoblastoma protein hyperphosphorylation and E2F transcription factor activation. BRK1 thus emerges as an angiogenic growth factor linking myeloid cell death to ischemic tissue repair and potentially enabling a protein-based therapy for myocardial infarction.
2025-11-11 | GSE291736 | GEO
Project description:Affymetrix microarray analysis of molecular changes after myocardial infarction. Samples of heart tissue were analyzed after myocardial infarction from WT and reg3beta knock-out mice. Samples from scar tissue and samples adjacent to the scar were analyzed. In the experiment we primarily compared infarction zone of wild-type to infarction zone of knock-out animals, and remote zone of wild-type to remote zone of knock-outs.
2015-06-29 | E-MTAB-2561 | biostudies-arrayexpress
Project description:Ischemic heart failure after acute myocardial infarction (AMI) is a major cause of morbidity and mortality worldwide. We recently reported that activation of a trans-valvular axial-flow pump in the LV and delaying myocardial reperfusion, known as Primary Unloading, limits infarct size by reducing LV wall stress and increasing expression of the cardioprotective cytokine, stromal derived factor 1 alpha (SDF1a). The mechanisms underlying the cardioprotective benefit and sustained effect of Primary Unloading remain poorly understood. We now tested the importance of delayed reperfusion, the functional significance of SDF1a, and the late-term impact on myocardial function and scar size associated with Primary Unloading. Adult male swine were subjected to Primary Reperfusion or Primary Unloading after 90 minutes of left anterior descending artery occlusion. Compared to Primary Reperfusion, 30 minutes of Primary Unloading was necessary and sufficient prior to reperfusion to limit infarct size. Primary Unloading was associated with a global shift in gene expression within the infarct zone favoring cardioprotection. Compared to Primary Reperfusion, Primary Unloading for 30 minutes preserved SDF1a protein levels without changing SDF1a mRNA levels within the infarct zone and further promoted a shift towards anti-apoptotic signaling within the infarct zone. Primary Unloading reduced activity levels of proteases known to degrade SDF1a and blocking the SDF1a receptor, CXCR4, attenuated the cardioprotective effect of Primary Unloading. Primary Unloading further reduced LV scar size, improved cardiac function, limited expression of markers associated with heart failure and maladaptive remodeling within the non-infarct zone 28 days after acute myocardial infarction. In conclusion, we introduce that Primary Unloading for 30 minutes before, not after reperfusion limits infarct size, increases SDF1a levels within the infarct zone, and results in a durable reduction in LV scar size, improved cardiac function, and limits markers of heart failure and maladaptive remodeling 28 days after AMI.
2018-10-25 | GSE108644 | GEO
Project description:We want to find that the TREM2 mechanism on the Macrophages in the myocardial infarction
2022-11-15 | GSE218002 | GEO
Project description:Extracellular BRICK1 drives heart repair after myocardial infarction
| PRJNA1235165 | ENA
Project description:Despite a substantial progress in diagnosis and therapy, acute myocardial infarction (MI) is a major cause of mortality in the general population. A novel insight into the pathophysiology of myocardial infarction obtained by studying gene expression should help to discover novel biomarkers of MI and to suggest novel strategies of therapy. The aim of our study was to establish gene expression patterns in leukocytes from acute myocardial infarction patients. ST-segment elevation myocardial infarction alters expression of several groups of genes. On admission, several genes and pathways that could be directly or indirectly linked with lipid/glucose metabolism, platelet function and atherosclerotic plaque stability were affected (signaling of PPAR, IL-10, IL-6). Analysis at discharge highlighted specific immune response (upregulation of immunoglobulins). Highly significant and substantial upregulation of SOCS3 and FAM20 genes expression in the first 4-6 days of myocardial infarction in all patients is the most robust observation of our work Twenty-eight patients with ST-segment elevation myocardial infarction (STEMI) were included. The blood was collected on the 1st day of myocardial infarction, after 4-6 days, and after 6 months. Control group comprised 14 patients with stable coronary artery disease (CAD), without history of myocardial infarction. Gene expression analysis was performed with Affymetrix GeneChipM-BM-. Human Gene 1.0 ST microarrays and GCS3000 TG system.
2014-10-23 | E-GEOD-62646 | biostudies-arrayexpress
Project description:The Myocardial Infarction Platelet Transcriptome
| PRJNA1135265 | ENA
Project description:Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells after experimental myocardial infarction revealed increased expression of monocyte chemoattractant proteins. In parallel, myocardial infarction increased crosstalk between brain-resident myeloid cells and oligodendrocytes, leading to neuroinflammation, white matter injury, and cognitive dysfunction. Inhibition of monocyte recruitment preserved white matter integrity and cognitive function, linking monocytes to neurodegeneration after myocardial infarction. Together, these preclinical and clinical results demonstrate that monocyte infiltration into the brain after myocardial infarction initiate neuropathological events that lead to vascular dementia.
2025-05-21 | GSE268156 | GEO