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Next Generation Sequencing Facilitates Quantitative Analysis of human umbilical vein endothelial cell(HUVEC) with and without treatment of CHIR99021+FGF1

ABSTRACT: The mortality of patients suffering from acute myocardial infarction (AMI) is linearly related to the infarct size. As regeneration of cardiomyocytes from cardiac progenitor cells is minimal in the mammalian adult heart, we have explored a new therapeutic approach which leverages the capacity of nanomaterials to release chemicals over time to promote myocardial protection and infarct size reduction. Initial screening identified two chemicals, FGF1 and CHIR99021 (a Wnt1 agonist/GSK-3 antagonist) which synergistically enhance cardiomyocyte cell cycle in vitro. Poly-lactic-co-glycolic acid (PLGA) nanoparticles (NP) formulated with CHIR99021 and FGF1 (CHIR+FGF1-NPs) provided an effective slow release system for up to 4 weeks. Intramyocardial injection of CHIR+FGF1-NPs enabled myocardial protection via reducing infarct size by 20-30% in mouse or pig models of postinfarction LV remodeling. This LV structural improvement was accompanied by a significant preservation of cardiac contractile function. Further investigation revealed that CHIR+FGF1-NPs resulted in a significant reduction of cardiomyocyte apoptosis and increase of angiogenesis. Thus, using a combination of chemicals and a NP-based prolonged release system that work synergistically, this study demonstrates a novel therapy for LV infarct size reduction in hearts with acute myocardial infarction.

ORGANISM(S): Homo sapiens

PROVIDER: GSE138837 | GEO | 2019/10/17

REPOSITORIES: GEO

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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.

Project description:Coronary heart disease is the leading cause of death worldwide. After an acute myocardial infarction, early reperfusion reduces infarct size, which correlates with improved clinical outcomes. Paradoxically, reperfusion although relieving ischemia, accelerates apoptosis in injured cardiomyocytes, which has led to the view that myocardial salvage is futile beyond the first few hours of reperfusion. In murine hearts subjected to 90 min of coronary artery occlusion and then 48 h of reperfusion, we show transient activation of intrinsic prosurvival insulin-like growth factor-1 (IGF-1) signaling. In these hearts, acute IGF-1 receptor inhibition decreases the abundance of prosurvival signaling molecules, and markedly activates caspase-3, a potent effector of apoptosis, in infarct border zone cardiomyocytes. We found that mouse mast cell protease-4 (MMCP-4) degraded IGF-1 in vitro by a novel catalytic activity of chymases. In vivo, this degradation, which is triggered by mast cell infiltration into the peri-infarct region and MMCP-4 extravasation, between 48 and 72 h post-ischemia/reperfusion (I/R), attenuates IGF-1 prosurvival signaling. In MMCP-4-deficient mice, while infarct size is not reduced at 24 h post-I/R, at 72 h post-I/R myocardial IGF-1 levels and signaling are increased, resulting in activation of the survival kinases Akt and ERK, inhibition of caspase-3, and reduced myocardial cell death. As a consequence, I/R-mediated loss of viable myocardium, adverse cardiac remodeling and contractile impairment are markedly reduced. Cardiomyocyte survival with consequent myocardial salvage may thus be possible even days after an ischemic insult, making them a novel therapeutic target for delayed cardioprotective therapy. Group 1 is wild type C57Bl6 uninjured hearts. These mice were not undergone any surgery and used as controls. Group 2 are wild type C57Bl6 72 h post-ischemia reperfusion (IR) injury hearts. These mice for subjected to ischemia reperfusion (IR) involving 90 min of left anterior descending coronary artery occlusion followed by reperfusion for 3 days or 72 h.

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Next Generation Sequencing Facilitates Quantitative Analysis of human umbilical vein endothelial cell(HUVEC) with and without treatment of CHIR99021+FGF1

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