MiR548ai antagonism attenuates exosome-induced endothelial cell dysfunction
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ABSTRACT:
PROVIDER: PRJNA770745 | ENA |
REPOSITORIES: ENA
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Project description:Endothelial cell (EC) and smooth muscle cell (SMC) are major cell types adjacent in the vascular wall. Recent progress indicates that their communication is crucial for vascular homeostasis and pathogenesis. In particular, dysfunctional (proliferative) SMCs through exosomes can induce EC dysfunction (impaired growth). The current study suggests that miR548ai, a rarely known microRNA, may provide a molecular target for protection against SMC/exosome-induced EC dysfunction. We performed microarray profiling of microRNAs of dysfunctional human primary aortic SMCs induced by different cytokines (PDGF-BB, TGFβ1, TNFα, IL1β). Among the microRNAs commonly upregulated by these cytokines, miR548ai showed the most robust changes, as also validated through quantitative PCR. This cytokine-induced miR548ai upregulation was recapitulated in the qPCR determination of SMC-derived exosomal microRNAs. Consistent with SMC-to-EC communication, the exosomes extracted from cytokine-stimulated SMCs impaired human EC proliferation and migration. Of particular interest, this SMC exosomal impingement on ECs was countered by transfection of miR548ai inhibitor microRNA into ECs. Furthermore, the miR548ai inhibitor transfected into SMCs attenuated SMC dysfunction/proliferation. Thus, these results identify miR548ai as a novel target; namely, miR548ai inhibitor mitigates EC dysfunction induced by exosomes derived from dysfunctional SMCs. This new knowledge may aid the future development of microRNA-based treatment of vascular disorders.
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Project description:We performed microarray profiling of microRNAs of dysfunctional human primary aortic SMCs induced by different cytokines (PDGF-BB, TGFβ1, TNFα, IL1β).
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Project description:Chromatin-associated RNA (caRNA) has been proposed as a type of epigenomic modifier. Here, we test whether environmental stress can induce cellular dysfunction through modulating RNA-chromatin interactions. We induce endothelial cell (EC) dysfunction with high glucose and TNFα (H + T), that mimic the common stress in diabetes mellitus. We characterize the H + T-induced changes in gene expression by single cell (sc)RNA-seq, DNA interactions by Hi-C, and RNA-chromatin interactions by iMARGI. H + T induce inter-chromosomal RNA-chromatin interactions, particularly among the super enhancers. To test the causal relationship between H + T-induced RNA-chromatin interactions and the expression of EC dysfunction-related genes, we suppress the LINC00607 RNA. This suppression attenuates the expression of SERPINE1, a critical pro-inflammatory and pro-fibrotic gene. Furthermore, the changes of the co-expression gene network between diabetic and healthy donor-derived ECs corroborate the H + T-induced RNA-chromatin interactions. Taken together, caRNA-mediated dysregulation of gene expression modulates EC dysfunction, a crucial mechanism underlying numerous diseases.
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Project description:Background: Cellular communication among different types of vascular cells is indispensable for maintenance of vascular homeostasis and prevention of atherosclerosis (AS). However, the biological mechanism involved in cellular communication among these cells and whether this biological mechanism can be used to treat AS remain unknown. This study hypothesizes that endothelial autophagy mediates the cellular communication of vascular tissue through exosome-mediated delivery of AS-related genes.Methods: ApoE-/- mice fed with high-fat diet (HFD) were received rapamycin to activate autophagy, or were intravenously injected with adeno-associated virus (AAV) vectors carrying shRNA against Atg7 mRNA under the Tie (tyrosine kinase) promoter to specifically inhibit endothelial autophagy. miRNA microarray, in vivo and in vitro experiments and human vascular tissues/blood vessels were used to explore the molecular mechanisms of atheroprotective effect of endothelial autophagy. Exosomes were isolated and characterized. Immunofluorescence and exosomes coculture experiments were conducted to examine the role of endothelial autophagy in regulating communication between endothelial cells (ECs) and smooth muscle cells (SMCs) via exosome.Results: Endothelial autophagy was inhibited in ECs of thoracic aortas in HFD fed ApoE-/- mice. Furthermore, rapamycin alleviated HFD-triggered atherosclerotic burden and endothelial dysfunction, while endothelial-specific depletion of Atg7 aggravated atherosclerotic burden. miRNA microarray, in vivo and in vitro experiments and human vascular tissues analysis revealed that endothelial autophagy alleviated endothelial dysfunction by downregulating miR-204-5p expression by directly targeting BCL2 to regulate apoptosis in ECs. Moreover, endothelial autophagy decreased miR-204-5p expression by loading this molecule into multivesicular bodies and secreting them out of cells via exosomes, and ECs-derived exosomal miR-204-5p could be transferred to SMCs, antagonized SMCs calcification.Conclusions: Our study first revealed that endothelial autophagy was a critical regulator of atherogenesis by transferring miR-204-5p from ECs to SMCs by exosomes, and endothelial autophagy activation by rapamycin, could alleviate AS in a “one stone hit two birds” manner.
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Project description:Chromatin-associated RNA (caRNA) has been proposed as a type of epigenomic modifier. Here, we test whether environmental stress can induce cellular dysfunction through modulating RNA-chromatin interactions. We induce endothelial cell (EC) dysfunction with high glucose and TNFα (H + T), that mimic the common stress in diabetes mellitus. We characterize the H + T-induced changes in gene expression by single cell (sc)RNA-seq, DNA interactions by Hi-C, and RNA-chromatin interactions by iMARGI. H + T induce inter-chromosomal RNA-chromatin interactions, particularly among the super enhancers. To test the causal relationship between H + T-induced RNA-chromatin interactions and the expression of EC dysfunction-related genes, we suppress the LINC00607 RNA. This suppression attenuates the expression of SERPINE1, a critical pro-inflammatory and pro-fibrotic gene. Furthermore, the changes of the co-expression gene network between diabetic and healthy donor-derived ECs corroborate the H + T-induced RNA-chromatin interactions. Taken together, caRNA-mediated dysregulation of gene expression modulates EC dysfunction, a crucial mechanism underlying numerous diseases.
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Project description:Chromatin-associated RNA (caRNA) has been proposed as a type of epigenomic modifier. Here, we test whether environmental stress can induce cellular dysfunction through modulating RNA-chromatin interactions. We induce endothelial cell (EC) dysfunction with high glucose and TNFα (H + T), that mimic the common stress in diabetes mellitus. We characterize the H + T-induced changes in gene expression by single cell (sc)RNA-seq, DNA interactions by Hi-C, and RNA-chromatin interactions by iMARGI. H + T induce inter-chromosomal RNA-chromatin interactions, particularly among the super enhancers. To test the causal relationship between H + T-induced RNA-chromatin interactions and the expression of EC dysfunction-related genes, we suppress the LINC00607 RNA. This suppression attenuates the expression of SERPINE1, a critical pro-inflammatory and pro-fibrotic gene. Furthermore, the changes of the co-expression gene network between diabetic and healthy donor-derived ECs corroborate the H + T-induced RNA-chromatin interactions. Taken together, caRNA-mediated dysregulation of gene expression modulates EC dysfunction, a crucial mechanism underlying numerous diseases.
2020-08-17 | GSE135356 | GEO