Progesterone Changes the Pregnancy-Induced Adaptation of Cardiomyocyte Kv2.1 Channels via MicroRNA-29b.

The cardiovascular system adaptation occurs during pregnancy to ensure adequate maternal circulation. Progesterone (P4) is widely used in hormone therapy to support pregnancy, but little is known about its effects on maternal cardiac function. In this study, we investigated the cardiac repolarization and ion channel expression in pregnant subjects and mice models and studied the effects of P4 administrations on these pregnancy-mediated adaptations. P4 administrations shortened the prolongation of QTC intervals and action potential duration (APD) that occurred during pregnancy, which was mainly attributable to the reduction in the voltage-gated potassium (Kv) current under basal conditions. In vitro studies indicated that P4 regulated the Kv2.1 channel in a bidirectional manner. At a low dose (1 µM), P4 induced upregulation of Kv2.1 through P4 receptor, while at a higher dose (5 µM), P4 downregulated Kv2.1 by targeting microRNA-29b (miR-29b). Our data showed that P4 modulated maternal cardiac repolarization by regulating Kv2.1 channel activity during pregnancy. Kv2.1, as well as miR-29b, might be used as potential therapeutic targets for adaptations of the maternal cardiovascular system or evaluation of progesterone medication during pregnancy.

Circular RNA profiling reveals a potential role of hsa_circ_IPCEF1 in papillary thyroid carcinoma.

Circular RNAs (circRNAs) are a novel type of non­coding RNAs that are expressed across species and are implicated in cellular biological processes, displaying dysregulated expression in various tumorigeneses. Therefore, circRNA deregulation could be a crucial event in thyroid carcinoma. The present study identified circRNA signatures in several patients with papillary thyroid carcinoma (PTC) to complement the understanding of PTC pathogenesis. Using microarray technology, the circRNA profiles in three pairs of PTC tumors and matching adjacent normal tissues were screened. Differentially expressed circRNAs were further validated by reverse transcription­quantitative PCR in whole blood from 57 pairs of subjects. Bioinformatics data analyses including miRNA response element prediction, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway, competing endogenous RNA and KEGG Orthology­Based Annotation System analyses were performed to predict circRNA associations with cancer­related putative downstream miRNAs and target genes. Receiver operating characteristic curves and the area under the curve (AUC) values were acquired to assess the performance of validated circRNAs in predicting potential associations with PTC. In total, 158 dysregulated circRNAs were identified in PTC tumors relative to adjacent normal tissues. Notably, one downregulated circRNA (hsa_circ_IPCEF1) showed the preferable predictive power (AUC=0.8010, P<0.0001) and interactions with four cancer­related genes (CASR, CDC25B, NFκB1 and SHOC2). From these analyses, one PTC­related miRNA (hsa­miR­3619­5p) was identified as a potential target for hsa_circ_IPCEF1 sponging, indicating the hsa_circ_IPCEF1/hsa­miR­3619­5p axis in pathogenesis.

hsa_circNFXL1_009 modulates apoptosis, proliferation, migration, and potassium channel activation in pulmonary hypertension.

In this study, we explored the circular RNA (circRNA) profile in pulmonary arterial hypertension (PAH) patients caused by chronic obstructive pulmonary disease (COPD) and the effects of hsa_circNFXL1_009 on abnormal proliferation, apoptosis, and migration of human pulmonary arterial smooth muscle cells (hPASMCs) driven by hypoxia. Using microarrays, we screened the circRNA profile in whole-blood samples from three pairs of subjects and found 158 dysregulated circRNAs in patients with PAH-COPD. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis further validated that hsa_circNFXL1_009 was dramatically downregulated with the highest area under a receiver operating characteristic curve (ROC) in 21 pairs of subjects. Consistently, exposure to hypoxia markedly reduced the hsa_circNFXL1_009 level in cultured hPASMCs. Delivery of exogenous hsa_circNFXL1_009 attenuated hypoxia-induced proliferation, apoptotic resistance, and migration of hPASMCs, as evidenced by immunocytochemistry, 5-ethynyl-2'-deoxyuridine incorporation, wound healing, and a TUNEL (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling) assay. A luciferase assay showed that hsa_circNFXL1_009 directly sponged hsa-miR-29b-2-5p (miR-29b) and positively regulated the expression of voltage-gated potassium (K+) channel subfamily B member 1 (KCNB1) at the mRNA level. Using patch-clamp electrophysiology, we proved that overexpression of hsa_circNFXL1_009 promoted a whole-cell K+ current in hPASMCs. Taken together, these studies identify hsa_circNFXL1_009 as a key regulator of PAH, and it may be used as a potential therapeutic target for the treatment of PAH.