This study was aimed at investigating the effects of lncRNA AK139328 on myocardial ischaemia/reperfusion injury (MIRI) in diabetic mice. Ischaemia/reperfusion (I/R) model was constructed in normal ...mice (NM) and diabetic mice (DM). Microarray analysis was utilized to identify lncRNA AK139328 overexpressed in DM after myocardial ischaemia/reperfusion (MI/R). RT‐qPCR assay was utilized to investigate the expressions of lncRNA AK139328 and miR‐204‐3p in cardiomyocyte and tissues. Left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF) and fractioning shortening (FS) were obtained by transthoracic echocardiography. Haematoxylin‐eosin (HE) staining and Masson staining were utilized to detect the damage of myocardial tissues degradation of myocardial fibres and integrity of myocardial collagen fibres. Evans Blue/TTC staining was used to determine the myocardial infarct size. TUNEL staining was utilized to investigate cardiomyocyte apoptosis. The targeted relationship between lncRNA AK139328 and miR‐204‐3p was confirmed by dual‐luciferase reporter gene assay. MTT assay was used for analysis of cardiomyocyte proliferation. Western blot was utilized to investigate the expression of alpha smooth muscle actin (α‐SMA), Atg7, Atg5, LC3‐II/LC3‐I and p62 marking autophagy. Knockdown of lncRNA AK139328 relieved myocardial ischaemia/reperfusion injury in DM and inhibited cardiomyocyte autophagy as well as apoptosis of DM. LncRNA AK139328 modulated miR‐204‐3p directly. MiR‐204‐3p and knockdown of lncRNA AK139328 relieved hypoxia/reoxygenation injury via inhibiting cardiomyocyte autophagy. Silencing lncRNA AK139328 significantly increased miR‐204‐3p expression and inhibited cardiomyocyte autophagy, thereby attenuating MIRI in DM.
Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving ...complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual's genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine "genomic plasticity," i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual's physiology and developmental programming of health and disease later in life are discussed.
Hypoxia during pregnancy impairs uterine vascular adaptation via microRNA‐210 (miR‐210)‐mediated mitochondrial dysfunction and mitochondrial reactive oxygen species (mtROS) generation. TET ...methylcytosine dioxygenase 2 (TET2) participates in regulating inflammation and oxidative stress and its deficiency contributes to the pathogenesis of multiple cardiovascular diseases. Thus, we hypothesize a role of TET2 in hypoxia/miR‐210‐mediated mtROS suppressing spontaneous transient outward currents (STOCs) in uterine arteries. We found that gestational hypoxia downregulated TET2 in uterine arteries of pregnant sheep and TET2 was a target of miR‐210. Knockdown of TET2 with small interfering RNAs suppressed mitochondrial respiration, increased mtROS, inhibited STOCs and elevated myogenic tone. By contrast, overexpression of TET2 negated hypoxia‐ and miR‐210‐induced mtROS. The effects of TET2 knockdown in uterine arteries on mtROS, STOCs and myogenic contractions were blocked by the mitochondria‐targeted antioxidant MitoQ. In addition, the recovery effects of inhibiting endogenous miR‐210 with miR‐210‐LNA on hypoxia‐induced suppression of STOCs and augmentation of myogenic tone were reversed by TET2 knockdown in uterine arteries. Together, our study reveals a novel mechanistic link between the miR‐210‐TET2‐mtROS pathway and inhibition of STOCs and provides new insights into the understanding of uterine vascular maladaptation in pregnancy complications associated with gestational hypoxia.
Key points
Gestational hypoxia downregulates TET methylcytosine dioxygenase 2 (TET2) in uterine arteries of pregnant sheep.
TET2 is a downstream target of microRNA‐210 (miR‐210) and miR‐210 mediates hypoxia‐induced TET2 downregulation.
Knockdown of TET2 in uterine arteries recapitulates the effect of hypoxia and miR‐210 and impairs mitochondrial bioenergetics and increases mitochondrial reactive oxygen species (mtROS) .
Overexpression of TET2 negates the effect of hypoxia and miR‐210 on increasing mtROS.
TET2 knockdown reiterates the effect of hypoxia and miR‐210 and suppresses spontaneous transient outward currents (STOCs) and elevates myogenic tone, and these effects are blocked by MitoQ.
Knockdown of TET2 reverses the miR‐210‐LNA‐induced reversal of the effects of hypoxia on STOCs and myogenic tone in uterine arteries.
figure legend The study reveals a novel mechanistic link between the microRNA‐210‐TET2‐mtROS pathway and inhibition of spontaneous transient outward currents (STOCs) and provides new insights into the understanding of uterine vascular maladaptation in pregnancy complications associated with gestational hypoxia.
Background and Purpose
Hypoxia during pregnancy is associated with increased uterine vascular resistance and elevated blood pressure both in women and female sheep. A previous study demonstrated a ...causal role of microRNA‐210 (miR‐210) in gestational hypoxia‐induced suppression of Ca2+ sparks/spontaneous transient outward currents (STOCs) in ovine uterine arteries, but the underlying mechanisms remain undetermined. We tested the hypothesis that miR‐210 perturbs mitochondrial metabolism and increases mitochondrial reactive oxygen species (mtROS) that confer hypoxia‐induced suppression of STOCs in uterine arteries.
Experimental Approach
Resistance‐sized uterine arteries were isolated from near‐term pregnant sheep and were treated ex vivo in normoxia and hypoxia (10.5% O2) for 48 h.
Key Results
Hypoxia increased mtROS and suppressed mitochondrial respiration in uterine arteries, which were also produced by miR‐210 mimic to normoxic arteries and blocked by antagomir miR‐210‐LNA in hypoxic arteries. Hypoxia or miR‐210 mimic inhibited Ca2+ sparks/STOCs and increased uterine arterial myogenic tone, which were inhibited by the mitochondria‐targeted antioxidant MitoQ. Hypoxia and miR‐210 down‐regulated iron–sulfur cluster scaffold protein (ISCU) in uterine arteries and knockdown of ISCU via siRNAs suppressed mitochondrial respiration, increased mtROS, and inhibited STOCs. In addition, blockade of mitochondrial electron transport chain with antimycin and rotenone inhibited large‐conductance Ca2+‐activated K+ channels, decreased STOCs and increased uterine arterial myogenic tone.
Conclusion and Implications
This study demonstrates a novel mechanistic role for the miR‐210‐ISCU‐mtROS axis in inhibiting Ca2+ sparks/STOCs in the maladaptation of uterine arteries and provides new insights into the understanding of mitochondrial perturbations in the pathogenesis of pregnancy complications resulted from hypoxia.
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Key points
Gestational hypoxia represses ten–eleven translocation methylcytosine dioxygenase 1 (TET1) expression in uterine arteries, which is recovered by inhibiting endogenous miR‐210.
Inhibition ...of miR‐210 rescues BKCa channel expression and current in uterine arteries of pregnant animals acclimatized to high altitude hypoxia in a TET‐dependent manner.
miR‐210 blockade restores BKCa channel‐mediated relaxations and attenuates pressure‐dependent myogenic tone in uterine arteries of pregnant animals acclimatized to high altitude.
Gestational hypoxia at high altitude has profound adverse effects on the uteroplacental circulation, and is associated with increased incidence of preeclampsia and fetal intrauterine growth restriction. Previous studies demonstrated that suppression of large‐conductance Ca2+‐activated K+ (BKCa) channel function played a critical role in the maladaptation of uteroplacental circulation caused by gestational hypoxia. Yet, the mechanisms underlying gestational hypoxia‐induced BKCa channel repression remain undetermined. The present study investigated a causal role of microRNA‐210 (miR‐210) in hypoxia‐mediated repression of BKCa channel expression and function in uterine arteries using a sheep model. The results revealed that gestational hypoxia significantly decreased ten–eleven translocation methylcytosine dioxygenase 1 (TET1) expression in uterine arteries, which was recovered by inhibiting endogenous miR‐210 with miR‐210 locked nucleic acid (miR‐210‐LNA). Of importance, miR‐210‐LNA restored BKCa channel β1 subunit expression in uterine arteries, which was blocked by a competitive TET inhibitor, fumarate, thus functionally linking miR‐210 to the TET1–BKCa channel cascade. In addition, miR‐210‐LNA reversed hypoxia‐mediated suppression of BKCa channel function and rescued the effect of steroid hormones in upregulating BKCa channel expression and function in uterine arteries, which were also ablated by fumarate. Collectively, the present study demonstrates a causative effect of miR‐210 in the downregulation of TET1 and subsequent repression of BKCa channel expression and function, providing a novel mechanistic insight into the regulation of BKCa channel function and the molecular basis underlying the maladaptation of uterine vascular function in gestational hypoxia.
Key points
Gestational hypoxia represses ten–eleven translocation methylcytosine dioxygenase 1 (TET1) expression in uterine arteries, which is recovered by inhibiting endogenous miR‐210.
Inhibition of miR‐210 rescues BKCa channel expression and current in uterine arteries of pregnant animals acclimatized to high altitude hypoxia in a TET‐dependent manner.
miR‐210 blockade restores BKCa channel‐mediated relaxations and attenuates pressure‐dependent myogenic tone in uterine arteries of pregnant animals acclimatized to high altitude.
Hypoxia is a common and severe stress to an organism's homeostatic mechanisms, and hypoxia during gestation is associated with significantly increased incidence of maternal complications of ...preeclampsia, adversely impacting on the fetal development and subsequent risk for cardiovascular and metabolic disease. Human and animal studies have revealed a causative role of increased uterine vascular resistance and placental hypoxia in preeclampsia and fetal/intrauterine growth restriction (FGR/IUGR) associated with gestational hypoxia. Gestational hypoxia has a major effect on mitochondria of uteroplacental cells to overproduce reactive oxygen species (ROS), leading to oxidative stress. Excess mitochondrial ROS in turn cause uteroplacental dysfunction by damaging cellular macromolecules, which underlies the pathogenesis of preeclampsia and FGR. In this article, we review the current understanding of hypoxia-induced mitochondrial ROS and their role in placental dysfunction and the pathogenesis of pregnancy complications. In addition, therapeutic approaches selectively targeting mitochondrial ROS in the placental cells are discussed.
Miniature inverted-repeat transposable elements (MITEs) are prevalent in eukaryotic species including plants. MITE families vary dramatically and usually cannot be identified based on homology. In ...this study, we de novo identified MITEs from 41 plant species, using computer programs MITE Digger, MITE-Hunter and/or Repetitive Sequence with Precise Boundaries (RSPB). MITEs were found in all, but one (Cyanidioschyzon merolae), species. Combined with the MITEs identified previously from the rice genome, >2.3 million sequences from 3527 MITE families were obtained from 41 plant species. In general, higher plants contain more MITEs than lower plants, with a few exceptions such as papaya, with only 538 elements. The largest number of MITEs is found in apple, with 237 302 MITE sequences. The number of MITE sequences in a genome is significantly correlated with genome size. A series of databases (plant MITE databases, P-MITE), available online at http://pmite.hzau.edu.cn/django/mite/, was constructed to host all MITE sequences from the 41 plant genomes. The databases are available for sequence similarity searches (BLASTN), and MITE sequences can be downloaded by family or by genome. The databases can be used to study the origin and amplification of MITEs, MITE-derived small RNAs and roles of MITEs on gene and genome evolution.
MicroRNAs (miRNAs) are small noncoding RNAs functioning as crucial post-transcriptional regulators of gene expression involved in cardiovascular development and health. Recently, mitochondrial miRNAs ...(mitomiRs) have been shown to modulate the translational activity of the mitochondrial genome and regulating mitochondrial protein expression and function. Although mitochondria have been verified to be essential for the development and as a therapeutic target for cardiovascular diseases, we are just beginning to understand the roles of mitomiRs in the regulation of crucial biological processes, including energy metabolism, oxidative stress, inflammation, and apoptosis. In this review, we summarize recent findings regarding how mitomiRs impact on mitochondrial gene expression and mitochondrial function, which may help us better understand the contribution of mitomiRs to both the regulation of cardiovascular function under physiological conditions and the pathogenesis of cardiovascular diseases.
• Family 1 glycosyltransferases comprise the greatest number of glycosyltransferases found in plants. The widespread occurrence and diversity of glycosides throughout the plant kingdom underscore the ...importance of these glycosyltransferases. • Here, we describe the identification and characterization of a late‐flowering Arabidopsis (Arabidopsis thaliana) mutant, in which a putative family 1 glycosyltransferase gene, UGT87A2, was disrupted. The role and possible mechanism of UGT87A2 in the regulation of flowering were analyzed by molecular, genetic and cellular approaches. • The ugt87a2 mutant exhibited late flowering in both long and short days, and its flowering was promoted by vernalization and gibberellin. Furthermore, the mutant flowering phenotype was rescued by the wild‐type UGT87A2 gene in complementation lines. Interestingly, the expression of the flowering repressor FLOWERING LOCUS C was increased substantially in the mutant, but decreased to the wild‐type level in complementation lines, with corresponding changes in the expression levels of the floral integrators and floral meristem identity genes. The expression of UGT87A2 was developmentally regulated and its protein products were distributed in both cytoplasm and nucleus. • Our findings imply that UGT87A2 regulates flowering time via the flowering repressor FLOWERING LOCUS C. These data highlight an important role for the family 1 glycosyltransferases in the regulation of plant flower development.
Postoperative sore throat (POST) is one of the most reported complications after general anesthesia with an incidence of as high as 60% which may impact patient satisfaction and increase the cost of ...treatment. The aim of this review is to summarize the currently accepted approaches and new trends intended to reduce the risk and increase the treatment efficacy of POST. Difficult intubation, traumatic intubation, and several other factors contribute to the development of POST. Endotracheal intubation using a stylet-loaded tube exerts excessive pressure on the anterior tracheal wall predisposing to mucosal trauma and contributing to development of POST. Pharmacological interventions are aimed at prevention, amelioration of symptoms, and treatment of POST. Medications suggested for this purpose include corticosteroids, topical sprays and creams, non-steroidal anti-inflammatory drugs (NSAID), and N-methyl-D-aspartate (NMDA) receptor antagonists. The use of video-laryngoscopes (VL) for endotracheal intubation improves the glottic view and increases the success rates with less force required to ensure adequate laryngoscopic view. Nevertheless, despite advances in laryngoscopic devices, the incidence of POST remains high. A novel intubation technique with endotracheal tube (ETT) rotation 180 degrees (ETT 180°) has been suggested to overcome stylet related injury and, possibly, decrease the POST. To date, no clinical trials have been conducted to test the efficacy of ETT 180° in reducing the incidence of POST. Undoubtedly, the suggested method deserves further investigation to determine its role in patient care.
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