The Circular RNA Cdr1as Promotes Myocardial Infarction by Mediating the Regulation of miR-7a on Its Target Genes Expression

Abstract

ObjectivesRecent studies have demonstrated the role of Cdr1as (or CiRS-7), one of the well-identified circular RNAs (circRNAs), as a miR-7a/b sponge or inhibitor in brain tissues or islet cells. This study aimed to investigate the presence of Cdr1as/miR-7a pathway in cardiomyocytes, and explore the mechanism underlying the function of miR-7a in protecting against myocardial infarction (MI)-induced apoptosis.MethodsMouse MI injury model was established and evaluated by infarct size determination. Real-time PCR was performed to quantify the expression of Cdr1as and miR-7a in cardiomyocytes. Cell apoptosis was determined by caspase-3 activity analysis and flow cytometry assays with Annexin V/PI staining. Transfection of Cdr1as overexpressing plasmid and miR-7a mimic were conducted for gain-of-function studies. Luciferase reporter assay and western blot analysis were performed to verity potential miR-7a targets.ResultsCdr1as and miR-7a were both upregulated in MI mice with increased cardiac infarct size, or cardiomyocytes under hypoxia treatment. Cdr1as overexpression in MCM cells promoted cell apoptosis, but was then reversed by miR-7a overexpression. The SP1 was identified as a new miR-7a target, in line with previously identified PARP, while miR-7a-induced decrease of cell apoptosis under hypoxia treatment was proven to be inhibited by PARP-SP1 overexpression. Moreover, Cdr1as overexpression in vivo increased cardiac infarct size with upregulated expression of PARP and SP1, while miR-7a overexpression reversed these changes.ConclusionsCdr1as also functioned as a powerful miR-7a sponge in myocardial cells, and showed regulation on the protective role of miR-7a in MI injury, involving the function of miR-7a targets, PARP and SP1.

CircRNA-Cdr1as Exerts Anti-Oncogenic Functions in Bladder Cancer by Sponging MicroRNA-135a

“…A previous study has reported that Cdr1as serves as a molecular sponge of miR-7 and conducts important functions in different biological or pathological progresses, including myocardial infarction [32], hepatocellular carcinoma [23], insulin transcription and secretion [22] and brain development [22]. We detected the expression of miR-7 and miR-135a in 29 pairs of bladder cancer tissues and ANTs.…”

Characteristic MicroRNA Expression Induced by δ-Opioid Receptor Activation in the Rat Liver Under Prolonged Hypoxia

“…Though none of these miRNAs are reported in current literature to be directly involved in hypoxia regulation in the liver, they do take part in functional regulation in other organs in hypoxia. For example, miR-7a-5p attenuates post-myocardial infarction remodeling and protects cardiac myocyte from hypoxia-induced apoptosis involving Sp1 and PARP-1 in mice [36-38] and miR-25 protects against hypoxia/reoxygenation-induced fibrosis and apoptosis in cardiomyocytes by targeting HMGB1 [39]. Also, miR-26 is induced in response to low oxygen and decreases proapoptotic signaling in a hypoxic environment [40], while miR-122-5p inhibition attenuates hypoxia/reoxygenation-induced myocardial cell apoptosis by targeting GATA4 [41].…”

The emerging role and clinical implication of human exonic circular RNA

“…The previously mentioned CDR1as, which mediates the regulation of miR-7 on its target gene expression, has also shown evidence of promoting myocardial infarctions (MIs). A study using MI mice to examine CDR1as and miR-7 demonstrated that CDR1as overexpression in myocardial muscle cells promoted cell apoptosis and that this effect can be reversed by miR-7 overexpression 24 . However, further mechanism to illustrate the CDR1as/miR-7 pathway during MI-induced apoptotic process need to be performed.…”

“…Genome-wide RNA-sequencing analyses have now identified a considerable number of circRNAs derived from backsplicing. Although they are generally expressed at low levels, increasing evidence has shown that circRNAs are linked to physiological development 15 and different diseases, such as neurological dystrophy, 21 cardiovascular diseases, [22][23][24][25] and cancer. [26][27][28] Recently, circRNAs have also been shown to be enriched and stable in plasma, 29 saliva, 30 and even in serum exosomes, 31 indicating the potential of circRNAs as readable biomarkers.…”