A series of anthracene-derived dyes for Cu2+-assisted CO sensing and bio-imaging: synthesis, performance, and mechanism.

Endogenous CO acts as an important messenger for signal transduction and therapeutic effect in the human body. Fluorescent imaging appears to be a promising method for endogenous CO recognition, but traditional luminescent probes based on Pd-complexes suffered from defects of high cost. In this work, four anthracene-derived dyes having an = N-N = group were synthesized for Cu2+-assisted CO sensing. Their molecular structure, photophysical performance and spectral response to Cu2+ and CO were analyzed in detail. The optimal probe showed good selectivity and quenching effect to Cu2+, with PLQY (photoluminescence quantum yield) decreased from 0.33 to 0.04. The quenching mechanism was found as a static quenching mechanism by forming a non-fluorescent complex with Cu2+ (stoichiometric ratio = 1:1), as revealed by single crystal, EPR (electron paramagnetic resonance), and XPS (X-ray photoelectron spectroscopy) analysis. Such quenching effect could be reversed by CO, showing recovered fluorescence, with PLQY recovered to 0.32 within 328 s. Discussion on cellular endogenous CO imaging was included as well.

Azoanthracene-core structure as Cu2+-assisted CO sensing probe: Characterization, performance, and bioimaging.

Detection of endogenous CO (carbon monoxide) is an interesting topic in biology because it has been discovered as a messenger for signal transduction and therapeutic effects in vital biological activities. Fluorescence imaging has proven a powerful tool for detecting endogenous CO, which drives the development of low-cost and easy-to-use fluorescent probes. In this study, four azobenzene derivatives (A1, A2, A3, and A4) with various substituents were reported, including their geometric structures, photophysical parameters, and spectral responses to Cu2+ and CO. The relationship between substituent structure and performance was discussed along with Cu2+ quenching and CO sensing mechanisms. The optimal probe (A1), which had no substituent, efficiently quenched fluorescence in the presence of Cu2+, with its PLQY decreased from 0.33 to 0.02, PLQY = photoluminescence quantum yield. Upon CO deoxidization, A1's fluorescence could be recovered (PLQY recovered to 0.32) within 180 s. Its sensing mechanism was static by forming a non-fluorescent complex with Cu2+ (with a stoichiometric ratio of 1:1). The bioimaging performance of A1 for endogenous CO in HeLa cells was reported.

Silencing of UTX Mitigates Aging-Associated Cardiac Fibrosis via Blocking Cardiac Fibroblasts-to-Myofibroblasts Trans-Differentiation.

BACKGROUND: Cardiac fibrosis increases with age. Fibroblast activation plays an essential role in cardiac fibrosis. Histone modifications are involved in various chromatin-dependent processes. Attenuation of the histone H3 trimethylation on lysine 27 demethylase UTX by RNA interference or heterozygous mutation extends lifespan in worm. The objective of this study was to explore whether epigenetic silencing of UTX mitigates aging-associated cardiac fibrosis. METHODS: Middle-aged mice (15 months old) were used and started to receive adeno-associated virus-scrambled-small hairpin RNA and adeno-associated virus-UTX-small hairpin RNA every 3 months from 15 months to 21 months, respectively. The mice were euthanized at 24 months of age (length of the study). RESULTS: Adeno-associated virus-UTX-small hairpin RNA delivery significantly attenu-ated aging-associated increase in blood pressure, especially in diastolic blood pressure, indicating silencing of UTX rescued aging-associated cardiac dysfunction. Aging-associated cardiac fibrosis is characterized by fibroblast activation and abundant extracellular matrix deposition, including collagen deposition and alpha smooth muscle actin activation. Silencing of UTX abolished collagen deposition and alpha smooth muscle actin activation, decreased serum transforming growth factor ß, blocked cardiac fibro blast s-to- myofi brobl asts trans-differentiation by elevation of cardiac resident mature fibroblast markers, TCF21, and platelet-derived growth factor receptor alpha, which are important proteins for maintaining cardiac fibroblast physiological function. In the mechanistic study, adeno-associated virus-UTX-small hairpin RNA blocked transforming growth factor ß-induced cardiac fibro blast s-to- myofi brobl asts trans-differentiation in isolated fibroblasts from 24-month-old mouse heart. The same results demonstrated as the in vivo study. CONCLUSIONS: Silencing of UTX attenuates aging-associated cardiac fibrosis via blocking cardiac fibroblasts-to-myofibroblasts transdifferentiation and consequently attenuates aging-associated cardiac dysfunction and cardiac fibrosis.

The Effect of Technical Training Provided by Agricultural Cooperatives on Farmers' Adoption of Organic Fertilizers in China: Based on the Mediation Role of Ability and Perception.

Organic fertilizers can be crucial in promoting sustainable agricultural development, but they are not used in a wide-ranging way among smallholder farmers in many developing countries. In China, cooperatives are considered essential subjects of agricultural technical training, but it is more common to join cooperatives without participating in their technical training. Thus, joining cooperatives or not cannot simply be used to assess the role of cooperatives in influencing the farmers' production behavior. Based on survey data of 1160 citrus farmers in Sichuan Province, China, this study estimated the effect of the technical training provided by agricultural cooperatives on farmers' adoption of organic fertilizers, taking into account the farmers' ability and perception as the mediation variables. The findings showed that participating in the technical training provided by agricultural cooperatives could significantly enhance the likelihood that farmers will adopt organic fertilizers. The impact was 81.6% in influencing the farmer's abilities and 7.64% in their perceptions of organic fertilizers. Furthermore, other variables, such as farm sizes, land transfers, and education levels, also make a difference in the effectiveness of the agricultural cooperatives' technical training. This study provides support for developing pertinent policies to promote the complete adoption of agricultural cooperatives' technical training functions and the widespread use of organic fertilizers.

Investigation of Specific Proteins Related to Different Types of Coronary Atherosclerosis.

Objective: Coronary heart disease (CHD) is a complex disease caused by multifaceted interaction between genetic and environmental factors, which makes identification of the most likely disease candidate proteins and their associated risk markers a big challenge. Atherosclerosis is presented by a broad spectrum of heart diseases, including stable coronary artery disease (SCAD) and acute myocardial infarction (AMI), which is the progressive stage of SCAD. As such, the correct and prompt diagnosis of atherosclerosis turns into imperative for precise and prompt disease diagnosis, treatment and prognosis. Methods: The current work aims to look for specific protein markers for differential diagnosis of coronary atherosclerosis. Thirty male patients between 45 and 55 years diagnosed with atherosclerosis were analyzed by tandem mass tag (TMT) mass spectrometry. The study excluded those who were additionally diagnosed with hypertension and type 1 and 2 diabetes. The Mufuzz analysis was applied to select target proteins for precise and prompt diagnosis of atherosclerosis, most of which were most related to high lipid metabolism. The parallel reaction monitoring (PRM) was used to verify the selected target proteins. Finally, The receiver operating characteristic curve (ROC) was calculated by a random forest experiment. Results: One thousand one hundred and forty seven proteins were identified in the TMT mass spectrometry, 907 of which were quantifiable. In the PRM study, six proteins related to lipid metabolism pathway were selected for verification and they were ALB, SHBG, APOC2, APOC3, APOC4, SAA4. Conclusion: Through the detected specific changes in these six proteins, our results provide accuracy in atherosclerosis patients' diagnosis, especially in cases with varying types of the disease.

Early application of extracorporeal membrane oxygenation for myocarditis with shock: a case report.

The current therapy for myocarditis is immunosuppressive therapy. However, in rare cases in which patients do not respond to intervention, their condition can rapidly deteriorate to myocarditis with shock, which is characterized by extensive and diffuse lymphocyte infiltration in the myocardium. Most cases of myocarditis are caused by virus-mediated damage of cardiomyocytes, and its clinical manifestations are ventricular arrhythmia and hemodynamic disturbances. Extracorporeal membrane oxygenation is an effective intervention, which regulates hemodynamic stability and avoids systemic hypoperfusion. This intervention has been used to sustain hemodynamic stability in patients with myocarditis and shock. We report here early application of extracorporeal membrane oxygenation for successful treatment of a patient with myocarditis and shock.

Long noncoding RNA MAPKAPK5-AS1 promoted lipopolysaccharide-induced inflammatory damage in the myocardium by sponging microRNA-124-3p/E2F3.

BACKGROUND: Myocardial dysfunction caused by sepsis (SIMD) leads to high mortality in critically ill patients. We investigated the function and mechanism of long non-coding RNA MAPKAPK5-AS1 (lncRNA MAPKAPK-AS1) on lipopolysaccharide (LPS)-induced inflammation response in vivo and in vitro. METHOD: Male SD rats were utilized for in vivo experiments. Rat cardiomyocytes (H9C2) were employed for in vitro experiments. Western blotting was employed to measure protein expression, and RT-PCR was performed to measure mRNA expression of inflammation factors. TUNEL and flow cytometry were carried out to evulate cell apoptosis. RESULT: The results showed that the expression of MAPKAPK5-AS1 was increased, while the expression of miR-124-3p was decreased in the inflammatory damage induced by LPS in vivo and in vitro. Knockdown of MAPKAPK5-AS1 reduced LPS-induced cell apoptosis and inflammation response, while overexpression of miR-124-3p weakened the effects of MAPKAPK5-AS1 knockdown on LPS-induced cell apoptosis and inflammation response. Moreover, miR-124-3p was identified as a downstream miRNA of MAPKAPK5-AS1, and E2F3 was a target of miR-214-3p. MAPKAPK5-AS1 knockdown increased the expression of miR-124-3p, while miR-124-3p overexpression reduced the expression of MAPKAPK5-AS1. In addition, miR-124-3p was found to downregulate E2F3 expression in H9C2 cells. CONCLUSION: MAPKAPK5-AS1/miR-124-3p/E2F3 axis regulates LPS-related H9C2 cell apoptosis and inflammatory response.

Optical Devices Constructed From Responsive Microgels for Polyphenols Detection.

Polyphenols are used as antioxidants in various foods and beverages, which are considered to be a health benefit. The measurement of polyphenols contents is of great interest in food chemistry and health science. This work reported a microgels based photonic device (etalon) to detect polyphenols. Dopamine was used as a model compound of polyphenols. Herein, we proposed a "block" concept for dopamine detection. The dopamine was oxidized and formed dopamine films catalyzed by tyrosinase on the surface of etalon. As the etalon was immersed in ZnCl2, the dopamine films blocked the ZnCl2 diffusion into etalon that caused optical property changes. The film thickness is associated with the concentration of dopamine which can be readout via optical signals.

Photophysical Details and O2-Sensing Analysis of a Eu(III) Complex in Polymer Composite Nanofibers Prepared by Electrospinning.

An as-synthesized Eu(III) complex, denoted as Eu(N-DPNQ)(TTD)3, was prepared and characterized, and the antenna mechanism between these ligands and central metal emitter was studied. Here DPNQ means 10-ethyl-10H-indolo [2',3':5,6]pyrazino[2,3-f][1,10]phenanthroline and TTD is 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione. We find that Eu(N-DPNQ)(TTD)3 emission intensity dependents on oxygen concentration, and O2-sensing skill of Eu(N-DPNQ)(TTD)3 in polymer composite nanofibers of poly (vinylpyrrolidone) (PVP) prepared by electrospinning is investigated. Results reveal that the emission quenching of Eu(N-DPNQ)(TTD)3 is caused by the ground state (triplet) oxygen quenching on antenna ligands triplet state. The Eu(N-DPNQ)(TTD)3 doped composite nanofiber with a loading level of 6 wt% exhibits the best result with sensitivity of 2.43 and response time of 10 s, along with linear response.

Suppression of miR-143-3p contributes to the anti-fibrosis effect of atorvastatin on myocardial tissues via the modulation of Smad2 activity.

Atorvastatin is a commonly prescribed statin drug for the control of lipid synthesis and recent studies have shown the cardiac protection potential of atorvastatin. Cardiac fibrosis is a critical process that impairs heart function. In the current study, the anti-fibrosis potential of atorvastatin was assessed and the mechanism associated with the treatment was explored. Fibrotic symptoms were induced using transverse aortic constriction (TAC) method in vivo and using TGF-ß1 in vitro. The effect of atorvastatin on the development of cardiac fibrosis was firstly measured. Moreover, the influence of miR-143-3p induction on the anti-fibrosis function of atorvastatin was determined. TAC administration induced cardiac fibrosis and heart weight increase, which was associated with the induced expressions of TGF-ß1, miR-143-3p, p-Smad2, and collagens. Atorvastatin restored the levels of TGF-ß1, miR-143-3p, p-Smad2, and collagens. The administration of TGF-ß1 induced the expressions of miR-143-3p, p-Smad2, and collagens in cardiac fibroblasts (CFs) and the effect was inhibited by atorvastatin. However, the function of atorvastatin was blocked by miR-143-3p mimics. The current study demonstrated that the suppression of miR-143-3p contributed to the anti-fibrosis effect of atorvastatin on myocardial tissues, which subsequently inhibited Smad2-mediated production of collagens.

Long noncoding RNA C2dat1 protects H9c2 cells against hypoxia injury by downregulating miR-22.

Myocardial ischemia is accompanied with hypoxia injury in myocardial cells. Long noncoding RNAs (lncRNA) CAMK2D-associated transcript 1 (C2dat1) C2dat1) has been linked with several ischemic diseases. However, the investigation regarding its role in myocardial ischemia is relatively rare. The aim of this study was to examine the role of C2dat1 in hypoxia response in H9c2 cells. H9c2 cells were subjected to hypoxia to evoke cell damage. Expressions of C2dat1, miR-22, and VEGF in H9c2 cells were altered by transfection, and then cell survival, migration, and invasion were respectively assessed posttransfection. Regulatory relationship between C2dat1, miR-22, and VEGF, as well as the involvement of PI3K/AKT/mTOR and JAK/STAT3 pathways in H9c2 cells injury was then studied. C2dat1 upregulation ameliorated hypoxia injury in H9c2 cells due to the increased viability, migration, and invasion, as well as the decreased apoptosis. miR-22 was negatively regulated by C2dat1. The effects of C2dat1 on H9c2 cells injured by hypoxia were attenuated when miR-22 was overexpressed. VEGF was a target gene of miR-22, and VEGF exerted similar protective effects to C2dat1. Finally, we found that silence of C2dat1 deactivated PI3K/AKT/mTOR and JAK/STAT3 pathways via regulating miR-22 and its downstream gene VEGF. C2dat1-miR-22-VEGF axis could regulate hypoxia injury in H9c2 cells. C2dat1 alleviated hypoxia injury possibly via downregulating miR-22, then upregulating VEGF, which further enhancing the activation of PI3K/AKT/mTOR and JAK/STAT3 pathways.

miR-34a-5p aggravates hypoxia-induced apoptosis by targeting ZEB1 in cardiomyocytes.

Myocardial infarction (MI) is an unsolved health problem which seriously affects human health around the world. miR-34a-5p acting as a tumor-suppressor is associated with left ventricular remodeling. We aimed to explore the functional roles of miR-34a-5p in cardiomyocytes. Hypoxia-induced cell injury in H9c2, HL-1 and human cardiac myocytes was analyzed according to the decrease of cell viability and increase of apoptosis. Expression of miR-34a-5p was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) when the concentration of O2 was decreased. Then, the effects of aberrantly expressed miR-34a-5p on proliferation and apoptosis of cardiomyocytes incubated under hypoxia were assessed. Finally, the downstream protein and signaling pathways of miR-34a-5p were explored. The hypoxic model was successfully constructed after incubation under hypoxia for 48 h. When the concentration of O2 decreased, the miR-34a-5p level was increased significantly. Then, we found miR-34a-5p aggravated hypoxia-induced alterations of proliferation and apoptosis in cardiomyocytes. Zinc finger E-box binding homeobox 1 (ZEB1) was identified as a target of miR-34a-5p, and miR-34a-5p conferred its function via targeting ZEB1. Finally, miR-34a-5p inhibition reversed hypoxia-induced decreases of phosphorylated kinases in the JAK/STAT and PI3K/AKT pathways through up-regulating ZEB1. Our study revealed that miR-34a-5p inhibition protected cardiomyocytes against hypoxia-induced cell injury through activating the JAK/STAT and PI3K/AKT pathways by targeting ZEB1.

The roles of PD-1/PD-L1 and its signalling pathway in gastrointestinal tract cancers.

Cancer immunotherapy has been increasingly applied in the treatment of advanced malignancies. Consequently, immune checkpoints have become a major concern. As PD-1 is an important immunomodulatory protein, the blockade of PD-1 and its ligand PD-L1 is a promising tumour immunotherapy for human carcinoma. In this review, we first discuss the role of the PD-1/PD-L1 interaction in gastrointestinal tract cancers. Targeting PD-1 and PD-L1 in immune cells and tumour cells may show remarkable efficiency in gastrointestinal tract cancers. Second, the PD-1/PD-L1-associated signalling pathway involved in cancer immunotherapy in gastrointestinal tract cancers is discussed. Most importantly, this review summarizes the PD-1/PD-L1-targeted immunotherapy combinations with relevant signalling pathways, which may result in a breakthrough for the treatment of gastrointestinal tract cancers, such as gastric cancer, colorectal cancer and liver cancer. Meanwhile, the review provides a deeper insight into the mechanism of checkpoint blockade immunotherapies.

Inhibition of microRNA-143-3p attenuates myocardial hypertrophy by inhibiting inflammatory response.

MicroRNA-143-3p (miR-143-3p) is involved in the initiation of inflammatory response and the progression of cardiovascular diseases. Myocardial hypertrophy is a common symptom in numerous cardiovascular diseases. In the current study, we attempted to demonstrate the role of miR-143-3p in the development of myocardial hypertrophy by focusing on its association with inflammation. Myocardial hypertrophy was induced by transverse aortic constriction (TAC) method in vivo and by H2 O2 administration in vitro. The expression status of miR-143-3p and downstream effectors were detected in animal heart tissues and H9c2 cells. Furthermore, the effect of miR-143-3p inhibition on H2 O2 -induced changes in ERK5/PPARδ/NF-κB axis was assessed. TAC induced oxidative stress and inflammation in rat heart tissues, which was associated with the increased expressions of miR-143-3p and p-ERK5. However, the up-regulated expression of miR-143-3p had no effect on the expression of ERK5, which was a direct target of miR-143-3p. The results of in vitro assays showed that H2 O2 administration increased the levels of miR-143-3p and p-EKR5 and induced the activation of NF-κB pathway. After the inhibition of miR-143-3p, the activation of EKR5 and NF-κB pathway was suppressed, whereas the expression of PPARδ was up-regulated. The current study demonstrated that miR-143-3p is crucial to the initiation of inflammatory response induced by myocardial hypertrophy. The activation of ERK5 following miR-143-3p up-regulation appears to be a complementary response to induce the subsequent anti-inflammatory signaling transduction, which needed further exploration.

Anti-hypertrophy effect of atorvastatin on myocardium depends on AMPK activation-induced miR-143-3p suppression via Foxo1.

Left ventricular hypertrophy (LVH) is a pathological characteristic shared by distinct heart disorders. Atorvastatin is employed as a lipid lowering agent and its heart protection effect has been recently reported as well. Thus, the current study attempted to validate the anti-hypertrophy effect of atorvastatin as well as the associated mechanism. Hypertrophic feature was induced in rats using transverse aortic constriction (TAC) method and in cardiomyocytes using angiotensin II (Ang II). Then the animals and cells were treated with atorvastatin and the effect on cardiac weight and structure as well as cell viability, surface area, and apoptosis was assessed. The mechanism associated with the anti-hypertrophy effect of atorvastatin was further explored by focusing on the AMPK/Foxo1/miR-143-3p axis. The results showed that the administration of atorvastatin significantly suppressed TAC-induced heart weight increase and attenuated cardiac structure deteriorations in rats. In in vitro assays, atorvastatin increased cell viability, and reduced cell surface area and apoptosis in Ang II-treated H9c2 cells. At molecular level, atorvastatin activated AMPK, which further promoted Foxo1 activation and suppressed miR-143-3p level. The key role of AMPK during atorvastatin treatment was further validated by subjecting Ang II-treated H9c2 cells to co-incubation of atorvastatin and Compound C, which blocked the pro-survival and anti-hypertrophy effect of atorvastatin on H9c2 cells. The findings outlined in the current study confirmed the anti-hypertrophy effect of atorvastatin and provided a preliminary explanation on the mechanism associated with the treatment: the protective effect of atorvastatin on myocardium against hypertrophy depended on miR-143-3p inhibition via AMPK and Foxo1 activation.

Ghrelin suppresses cardiac fibrosis of post-myocardial infarction heart failure rats by adjusting the activin A-follistatin imbalance.

Ghrelin, a growth hormone-releasing peptide, potentially improves cardiac function, but the mechanisms remain unclear. In the study, the rat heart failure (HF) model was established by ligating the left anterior descending coronary artery (LAD) and treated with ghrelin (100µg/kg, subcutaneous injection, bid); neonatal rat cardiomyocytes were cultured and stimulated with Ang II (0.1µM) and ghrelin(0.1µM) to explore the underlying mechanism of ghrelin in myocardial remodeling. Hemodynamic changes and serum brain natriuretic peptide (BNP) concentrations were measured to assess cardiac function. Left ventricular mass index (LVMI), hematoxylin and eosin (H&E) staining, and Masson's trichrome staining were performed to evaluate myocardial fibrosis. Interestingly, ghrelin significantly improved cardiac function by inhibiting fibrous tissue proliferation. To further explore the mechanisms by which ghrelin interferes with myocardial fibrosis, the levels of activin A (Act A) and its blocker-follistatin (FS) were examined by immunohistochemistry; Act A levels were significantly increased in the myocardial infarction (MI), and ghrelin administeration downregulated Act A expression. In contrast, FS expression showed no significant change in all experimental groups. Furthermore, ghrelin decreased Ang II-induced Act A expression with no effect on FS expression in primary rat cardiomyocytes in vitro (real-time quantitative PCR and ELISA). Thus, ghrelin corrected the Act A/FS imbalance. Finally, Act A treated cultured primary rat cardiac fibroblasts (CFs) showed increased proliferation [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay] and enhanced expressions of type I and type III collagen (Col I and Col III) (real-time quantitative PCR). These data suggest that ghrelin inhibits myocardial fibrosis, attenuates left ventricular remodeling, and eventually improves cardiac function by adjusting Act A/FS imbalance.

High expression of long chain acyl-coenzyme A synthetase 1 in peripheral blood may be a molecular marker for assessing the risk of acute myocardial infarction.

The current study aimed to investigate whether the increased expression of long chain acyl-coenzymeA synthetase 1 (ACSL1) in peripheral blood leukocytes (PBL) may be a molecular marker for the genetic evaluation of acute myocardial infarction (AMI). The mechanism of action of ACSL1 in the pathogenesis of AMI was also investigated. A total of 75 patients with AMI and 70 individuals without coronary heart disease were selected to participate in the present study. The demographic and clinical information of the enrolled subjects was recorded. Reverse transcription quantitative polymerase chain reaction and western blot analysis were applied to measure the expression of ACSL1 at the mRNA and protein levels. It was demonstrated that the expression of ACSL1 mRNA and protein in PBL was increased in patients with AMI compared with controls. Logistic regression analysis indicated that ACSL1 expression in PBL was an independent risk factor of AMI. There was a significant positive association between the level of ACSL1 expression and the degree of atherosclerosis in the coronary artery. Furthermore, patients with AMI exhibited an increased risk of atherosclerosis due to increased fasting blood glucose, total cholesterol, triglyceride and lipoprotein levels and decreased high-density lipoprotein levels, compared with controls. Therefore, the current study demonstrated that ACSL1 expression was increased in the PBLs of patients with AMI. The elevated expression of ACSL1 acts an independent risk factor of AMI and may act as a potential biomarker when determining the risk of AMI.

NOX2 Antisense Attenuates Hypoxia-Induced Oxidative Stress and Apoptosis in Cardiomyocyte.

Heart ischemia is a hypoxia related disease. NOX2 and HIF-1α proteins were increased in cardiomyocytes after acute myocardial infarction. However, the relationship of the hypoxia-induced HIF-1α. NOX2-derived oxidative stress and apoptosis in cardiomyocyte remains unclear. In the current study, we use NOX2 antisense strategy to investigate the role of NOX2 in hypoxia-induced oxidative stress and apoptosis in rat cardiomyocytes. Here, we show that transduction of ADV-NOX2-AS induces potent silencing of NOX2 in cardiomyocytes, and resulting in attenuation of hypoxia-induced oxidative stress and apoptosis. This study indicates the potential of antisense-based therapies and validates NOX2 as a potent therapeutic candidate for heart ischemia.

The human ATF1 rs11169571 polymorphism increases essential hypertension risk through modifying miRNA binding.

Activating transcription factor 1 (ATF1) may be involved in essential hypertension (EH) by induction of NADPH oxidase 1 (NOX1) and radical oxygen species (ROSs) production. Abnormal expression of ATF1 was found in EH in previous microarray analysis. Here we tested whether a single nucleotide polymorphism (SNP) located in the 3'-untranslated region (3'UTR) of ATF1 was associated with EH susceptibility by affecting microRNA (miRNA) binding. In silico analysis indicated that rs11169571 (T>C) was a candidate SNP to modulate miRNA: ATF1 mRNA complex, with the greatest changed energy for hsa-miR-1283, and the luciferase reporter analysis showed that miR-1283 inhibited the activity of the reporter vector carrying -T allele, but not the -C allele. In addition, inhibition of miR-1283 in HA-VSMCs enhanced the expression of ATF1 mRNA as well as the ROS levels. Further case-control study showed that rs11169571 was significantly associated with increased risk of EH. Finally, we observed an increased ATF1 protein level in peripheral blood of EH patients with CC carriers compared to TT carriers of rs11169571, with an intermediate ATF1 level in TC carriers. These results suggested that rs11169571 of ATF1 gene may be associated with EH, and the SNP-modified posttranscriptional gene regulation by miRNAs could be a potentially pathogenetic mechanism of EH.