Effect of Upy-PEG hydrogel injection and delivery of antimiR-195 on left ventricular transcriptome [baseline]
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ABSTRACT:
PROVIDER: PRJNA590358 | ENA |
REPOSITORIES: ENA
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Project description:Background MicroRNAs are potent regulators of biology and disease. The miR-15 family has been shown to regulate cardiomyocyte proliferation and antimiR-based inhibition induces a cardioprotective effect after myocardial infarction in mice. However, systemic delivery of antimiRs leads to accumulation in kidneys and liver, with relatively poor cardiac exposure. pH-responsive injectable hydrogels serve as a sustained-release drug delivery depot and could potentially be used to improve cardiac efficacy of antimiR therapeutics. Objective Examine whether hydrogel can improve local delivery of antimiR-195 in ischemic hearts to increase cardiac efficacy and limit off-target effects. Methods Study the effect of intramyocardial injections of hydrogel-formulated antimiR-195 under both baseline conditions and after ischemic injury. Results Intracardiac injections of UPy-PEG induced a transient inflammatory response that was no longer present 7 days post-injection. In vitro experiments showed that antimiR-195 was released from the gel, and induced microRNA inhibition leading to downstream cardiomyocyte proliferation. In vivo, intramyocardial delivery of antimiR-195 in UPy-PEG enhanced cardiac target de-repression compared to PBS-dissolved antimiR-195, despite a low cardiac retention. After ischemic injury, this translated into a greater therapeutic effect by increasing both target de-repression and cardiomyocyte proliferation. Conclusions UPy-PEG can be used as a cardiac delivery vehicle of antimiRs and intramyocardial injection of UPy-PEG formulated antimiR-195 is sufficient to improve cardiac efficacy of antimiR-195. Follow up experiments in large animals will enable us to assess the true added value of using UPy-PEG to increase cardiac exposure of antimiR therapies.
2022-11-19 | GSE140644 | GEO
Project description:Background MicroRNAs are potent regulators of biology and disease. The miR-15 family has been shown to regulate cardiomyocyte proliferation and antimiR-based inhibition induces a cardioprotective effect after myocardial infarction in mice. However, systemic delivery of antimiRs leads to accumulation in kidneys and liver, with relatively poor cardiac exposure. pH-responsive injectable hydrogels serve as a sustained-release drug delivery depot and could potentially be used to improve cardiac efficacy of antimiR therapeutics. Objective Examine whether hydrogel can improve local delivery of antimiR-195 in ischemic hearts to increase cardiac efficacy and limit off-target effects. Methods Study the effect of intramyocardial injections of hydrogel-formulated antimiR-195 under both baseline conditions and after ischemic injury. Results Intracardiac injections of UPy-PEG induced a transient inflammatory response that was no longer present 7 days post-injection. In vitro experiments showed that antimiR-195 was released from the gel, and induced microRNA inhibition leading to downstream cardiomyocyte proliferation. In vivo, intramyocardial delivery of antimiR-195 in UPy-PEG enhanced cardiac target de-repression compared to PBS-dissolved antimiR-195, despite a low cardiac retention. After ischemic injury, this translated into a greater therapeutic effect by increasing both target de-repression and cardiomyocyte proliferation. Conclusions UPy-PEG can be used as a cardiac delivery vehicle of antimiRs and intramyocardial injection of UPy-PEG formulated antimiR-195 is sufficient to improve cardiac efficacy of antimiR-195. Follow up experiments in large animals will enable us to assess the true added value of using UPy-PEG to increase cardiac exposure of antimiR therapies.
2022-11-19 | GSE140660 | GEO
Project description:Hydrogel-based intramyocardial delivery of antimiR-195
| PRJNA590475 | ENA
Project description:Hydrogel-based intramyocardial delivery of antimiR-195 after ischemia-reperfusion injury [UPyPEG_IR]
| PRJNA590477 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-11-19 | GSE140661 | GEO
Project description:Adverse mechanical cues promote pathological remodeling of ischemic left ventricle, which leads to heart failure and mortality in ischemic cardiomyopathy (ICM) patients. Intramyocardial injection of hydrogels reduces the mechanical stress in left ventricular (LV) wall, thus preserves cardiac function and geometry. The therapeutic concept has been tested in clinical trials and presented exciting potential. However, the theory of intramyocardial hydrogel injection still needs to be improved as the molecular biological connection between the mechanical effect and therapeutic outcomes is weak, and it is difficult to clearly separate the contribution of hydrogel mechanical support from physiological reaction to hydrogel chemistry and combinational surgical procedures in previous clinical translation studies. In this study, we transendocardially injected alginate hydrogel via a percutaneous coronary intervention in 10 ICM patients with end-stage heart failure. Thirty days after injection, cardiac function was improved, and LV size was reduced. Stress in the myocardium decreased as evaluated by finite element analysis. Similar mechanical and functional effects by hydrogel injections were observed in rat myocardial infarction (MI) model. Bulk and single-cell RNA sequencing revealed restoration in transcription levels of mechanosensing, cardiac contraction genes and other important pathways, which was mainly attributed to changes in cardiomyocytes. Such effects were not observed in rats receiving diluted hydrogel, confirming that mechanical effect instead of material chemistry is the main contributor. The resemblance in transcriptomic profile and the effect of hydrogel injection on mechanical stress and remodeling of LV wall between ICM patients and diseased rats indicated the applicability of the major mechanistic conclusions in rat model to human.
2024-08-01 | GSE253767 | GEO
Project description:RNA seq analysis on cardiac tissue samples 21 days after the intramyocardial injection of an acellular hydrogel in infarcted sheep hearts.
2021-01-05 | GSE164245 | GEO
Project description:Expression of the miR-34 family (miR-34a, -34b, -34c) is elevated in settings of heart disease, and inhibition with antimiR-34a/antimiR-34 has emerged as a promising therapeutic strategy. Under chronic cardiac disease settings, targeting the entire miR-34 family is more effective than targeting miR-34a alone. The identification of transcription factor (TF)-miRNA regulatory networks has added complexity to understanding the therapeutic potential miRNA-based therapies. Here, we sought to determine whether antimiR-34 targets secondary miRNAs via TFs which could contribute to antimiR-34-mediated protection. Using miRNA-Seq we identified differentially regulated miRNAs in hearts from mice with cardiac pathology due to transverse aortic constriction (TAC), and these miRNAs were also regulated by antimiR-34. Two clusters of stress-responsive miRNAs were classified as “pathological” and “cardioprotective”. Using ChIPBase we identified 45 TF binding sites on the promoters of “pathological” and “cardioprotective” miRNAs, and 5 represented direct targets of miR-34, with the capacity to regulate other miRNAs. The expression of two “pathological” miRNAs (let-7e and miR-31) was independently experimentally validated in hearts from antimiR-34 treated TAC mice, and may explain why targeting the entire miR-34 family is more effective than targeting miR-34a alone. AntimiR-34 regulates the expression of other miRNAs and this has significant implications for drug development.
2016-05-08 | GSE79050 | GEO
Project description:Adverse mechanical cues promote pathological remodeling of ischemic left ventricle, which leads to heart failure and mortality in ischemic cardiomyopathy (ICM) patients. Intramyocardial injection of hydrogels reduces the mechanical stress in left ventricular (LV) wall, thus preserves cardiac function and geometry. The therapeutic concept has been tested in clinical trials and presented exciting potential. However, the theory of intramyocardial hydrogel injection still needs to be improved as the molecular biological connection between the mechanical effect and therapeutic outcomes is weak, and it is difficult to clearly separate the contribution of hydrogel mechanical support from physiological reaction to hydrogel chemistry and combinational surgical procedures in previous clinical translation studies. In this study, we transendocardially injected alginate hydrogel via a percutaneous coronary intervention in 10 ICM patients with end-stage heart failure. Thirty days after injection, cardiac function was improved, and LV size was reduced. Stress in the myocardium decreased as evaluated by finite element analysis. Similar mechanical and functional effects by hydrogel injections were observed in rat myocardial infarction (MI) model. Bulk and single-cell RNA sequencing revealed restoration in transcription levels of mechanosensing, cardiac contraction genes and other important pathways, which was mainly attributed to changes in cardiomyocytes. Such effects were not observed in rats receiving diluted hydrogel, confirming that mechanical effect instead of material chemistry is the main contributor. The resemblance in transcriptomic profile and the effect of hydrogel injection on mechanical stress and remodeling of LV wall between ICM patients and diseased rats indicated the applicability of the major mechanistic conclusions in rat model to human.
2024-08-01 | GSE253763 | GEO
Project description:In order to better understand the context of root water stress and its relationship to other stresses, I undertook an evaluation of osmotic water stress by transcriptome analyses. Whole transcriptome MARSeq (Diego Adhemar Jaitin, 2017) analysis can enable us to study the changes in gene expression (changes in transcript prevalence) in depth under different treatments. It is a cost effective method to develop transcriptional activity. It uses relatively small amounts of RNA and reads sequences from the 3’-polyA containing end. This method can reveal underlying trends that can help us understand the less obvious processes happening in our system. To carry this out I processed whole transcriptome data separately from WT seedling roots exposure to PEG, and from roots under 30% PEG + 5mM HIS, 30% PEG + 1mM SHAM for 0, 1, 2, 3 h.
2021-05-26 | GSE152457 | GEO