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CircARHGAP12 triggers MSC autophagy to facilitate its effect on repairing diabetic wounds by sponging miR-301b-3p/ATG16L1 and miR-301b-3p/ULK2

ABSTRACT: Circular RNAs (circRNAs) have been found to play critical roles in the development and progression of human diseases. However, the role of circRNAs in regulating MSCs (mesenchymal stromal cells) to repair diabetic wounds remains unclear. Here, we showed that MSCs subjected to high glucose stress showed an obvious decrease in circARHGAP12, while circARHGAP12-mediated autophagy inhibited high glucose-induced apoptosis of MSCs. Mechanistically, circARHGAP12 could directly interact with miR-301b-3p, and subsequently act as a miRNA sponge to regulate the expression of the miR-301b-3p target genes ATG16L1 and ULK2 and the downstream signaling pathway. Furthermore, circARHGAP12 led to a decrease in apoptosis of MSCs in wounds and promoted wound healing. Taken together, these data indicated that circARHGAP12/ miR-301b-3p/ATG16L1 and ULK2 regulatory networks may be a potential therapeutic target for MSCs in repairing diabetic wounds.

ORGANISM(S): Homo sapiens

PROVIDER: GSE168890 | GEO | 2021/03/15

REPOSITORIES: GEO

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Project description:Background: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder, characterized by cardiomyocyte hypertrophy, cardiomyocyte disarray and fibrosis, which has a prevalence of ~1:200-500 and predisposes individuals to sudden death and heart failure. The mechanisms through which diverse HCM-causing mutations cause cardiac dysfunction remain mostly unknown and their identification may reveal new therapeutic avenues. MicroRNAs have emerged as critical regulators of gene expression and disease phenotype in various pathologies. We explored whether miRNAs could play a role in HCM pathogenesis and offer potential therapeutic targets. Methods and Results: Using high-throughput miRNA expression profiling and qPCR analysis in two distinct mouse models of HCM, we found that miR-199a-3p expression levels are upregulated in mutant mice compared to age- and treatment-matched wild-type mice. We also found that miR-199a-3p expression is enriched in cardiac non-myocytes compared to cardiomyocytes. When we expressed miR-199a-3p mimic in cultured primary cardiac non-myocytes and analyzed the conditioned media by proteomics, we found that several ECM proteins (e.g., TSP2, FBLN3, COL11A1, LYOX) were differentially expressed. We confirmed our proteomics findings by qPCR analysis of selected mRNAs and demonstrated that miR-199a-3p mimic expression in cardiac non-myocytes drives upregulation of ECM genes including Tsp2, Fbln3, Pcoc1, Col1a1 and Col3a1. To examine the role of miR-199a-3p in vivo, we inhibited its function using lock-nucleic acid (LNA)-based inhibitors (antimiR-199a-3p) in an HCM mouse model. Our results revealed that progression of cardiac fibrosis is attenuated when miR-199a-3p function is inhibited in mild-to-moderate HCM. Finally, guided by computational target prediction algorithms, we identified mRNAs Cd151 and Itga3 as direct targets of miR-199a-3p and have shown that miR-199a-3p mimic expression negatively regulates AKT activation in cardiac non-myocytes. Conclusions: Altogether, our results suggest that miR-199a-3p may contribute to cardiac fibrosis in HCM through its actions in cardiac non-myocytes. Thus, inhibition of miR-199a-3p in mild-to-moderate HCM may offer therapeutic benefit in combination with complementary approaches that target the primary defect in cardiac myocytes.

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CircARHGAP12 triggers MSC autophagy to facilitate its effect on repairing diabetic wounds by sponging miR-301b-3p/ATG16L1 and miR-301b-3p/ULK2

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