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Research Article HOTAIR Is a Potential Novel Biomarker in Patients with Congenital Heart Diseases

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Research Article HOTAIR Is a Potential Novel Biomarker in Patients with Congenital Heart Diseases Hindawi BioMed Research International Volume 2018, Article ID 2850657, 7 pages https://doi.org/10.1155/2018/2850657 Research Article HOTAIR Is a Potential Novel Biomarker in Patients with Congenital Heart Diseases Yu Jiang,1,2 Hongdan Mo,1,2 Jing Luo,1,2 Suhong Zhao,1,2 Shuang Liang,1,2 Maomao Zhang,1,2 and Jie Yuan 1,2 1 Department of Cardiology, Te Second Afliated Hospital of Harbin Medical University, Harbin 150001, China 2Te Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Heilongjiang Province 150001, China Correspondence should be addressed to Jie Yuan; [email protected] Received 5 October 2017; Revised 27 January 2018; Accepted 7 February 2018; Published 7 March 2018 Academic Editor: Diego Franco Copyright © 2018 Yu Jiang et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. To investigate the expression of HOX transcript antisense RNA (HOTAIR) in cardiac tissues and plasma of patients with congenital heart diseases (CHDs). Methods. qRT-PCR was used to detect the expression of HOTAIR in right atrial appendage tissues of 16 patients with CHDs and 14 patients with rheumatic valvular heart diseases (RVHDs), as well as in plasma of 36 normal people and 90 patients with CHDs including 36 cases of ASD, 23 cases of VSD, and 31 cases of PDA. Besides, the proteins interacting with HOTAIR were obtained from databases. Results. Te HOTAIR expression in cardiac tissues of CHDs group was signifcantly higher than that of the RVHDs group (� < 0.01). Compared with the control group, the expression of plasma HOTAIR in the ASD group, the VSD group, and the PDA group was all remarkably upregulated (� < 0.01), whereas there was no relationship between HOTAIR and pulmonary arterial hypertension and defects size. Databases show that HOTAIR is associated with polycomb repressive complex 2 (PRC2) which contributes to heart development. Conclusion.TelevelsofHOTAIRwereincreasedincardiac tissues and plasma of patients with CHDs. HOTAIR is a potential novel diagnostic biomarker in patients with CHDs. 1. Introduction HOX transcript antisense RNA (HOTAIR) is the frst transregulation lncRNA to be found. HOTAIR, which has Congenital heart disease (CHD) is the most common type a function of epigenetic regulation, has been shown to of congenital deformity and still represents an important be relevant to many diseases, such as multiple cancers, noninfectious cause of death in children [1]. CHD is widely osteoarthritis, and cardiovascular diseases [6]. Lots of stud- perceived to be a polygene heredity disease as a result of the ies have illustrated an important role of HOTAIR in car- complex interplay of genetic factors and environmental fac- diac diseases, including aortic valve calcifcation, cardiac tors in the early development of embryos, but its pathogenic hypertrophy, heart failure, and cardiac-associated sepsis [6– mechanism is still under research. A host of studies have 9]. However, little is known about the potential roles of shown that abnormal development of heart and vessels is HOTAIR in embryonic heart development. Terefore, in the associated with the mutation of many transcription factors present study we sought to determine the expression levels including Nkx2.5, GATA4, and Tbx5 [2]. Long noncoding of HOTAIR in cardiac tissues and plasma of patients with RNAs (lncRNAs) are defned as being noncoding RNA CHDs, establishing some bases for further research about the sequences of >200 nucleotides that can regulate target-gene function of HOTAIR on the embryonic heart development. expression, and they are closely related to malignant tumors, cardiovascular diseases, embryonic development, organism 2. Materials and Methods aging, and so on [3]. Mounting studies indicate that lncRNAs are new regulatory molecules involved in embryonic heart 2.1. Study Population. Te all-included cases with CHDs and development afer miRNAs [4, 5]. rheumatic valvular heart diseases (RVHDs) were derived 2 BioMed Research International from patients who had been diagnosed at the Second recentrifuged at 12000 rpm for 10 minutes. All steps were ∘ Afliated Hospital of Harbin Medical University, China, performed at 4 C. Plasma was then collected, divided into ∘ from November 2015 to June 2016. Human cardiac tissues aliquots, and stored frozen at −80 Cbeforeuse. were collected from 16 patients with CHDs and 14 patients with RVHDs who all required surgical treatment. Blood 2.5. RNA Isolation. Total plasma RNA was extracted from samples were collected from 90 patients with CHDs and 500 �l plasma using the Trizol (Invitrogen) according to the 36normalpeople.CHDsgroupsofbloodsampleswere manufacturer’s instruction and dissolved in 15 �lofdiethyl composed of 36 cases of atrial septal defect (ASD), 23 cases pyrocarbonate (DEPC) water. (i) Mix 500 �lplasmaand of ventricular septal defect (VSD), and 31 cases of patent 800 �lTrizol,andthenletitsitfor5minutesatroom ductus arteriosus (PDA). Te inclusion criteria of CHDs are temperature. (ii) Ten 160 �l chloroform was added. (iii) as follows: all cases were diagnosed with lef-to-right shunt Te mixture was centrifuged at 12000 rpm for 15 minutes CHDs (ASD, VSD, and PDA), the diagnosis was verifed by afer 15 minutes’ standing at room temperature. Ten 800 �l physical examination, X-ray, ECG, three-dimensional color supernatant was collected. (iv) Mix the supernatant with ∘ Doppler echocardiography, and the corrective operation. Te 800 �l isopropanol and let it sit for 4 hrs at −20 C. (v) Te healthy individuals were from center of health examination, mixture was centrifuged at 12000 rpm for 15 minutes, then the without a family history of CHDs and other congenital supernatant was discarded, and 1 ml 75% anhydrous ethanol malformation. Patients with CHDs were diagnosed by two (DEPC water preparation) was added to the centrifuge tube. cardiology experts with three-dimensional color Doppler. (vi) Repeat step (v). (vii) Te mixture was centrifuged at Exclusion criteria were as follows: (i) complex CHDs; (ii) 12000 rpm for 10 minutes, discarded the supernatant, dried patients with acute infection, serious heart valve disease, the white RNA precipitation at the bottom of the tube at room stroke, malignant tumor, severe liver and kidney disease, temperature for 5 minutes, and dissolved it in 16 �lDEPC and other severe systemic diseases; (iii) patients with use of water. Te concentration and purity of RNA were detected by immunosuppressant; (iv) patients with a history of recent ultraviolet spectrophotometer. Total RNA of cardiac tissues surgery and muscle damage which change the levels of was extracted from 50 mg tissues that were ground on ice lncRNAs; (v) patients who provided incomplete information; and the following steps were also carried out according to the (vi) patients who refused to participate in the study. Te manufacturer’s instruction. protocol was approved by the Ethics Committee of the Second Afliated Hospital of Harbin Medical University (Number 2.6. Primer Design and Quantitative Real-Time PCR Analysis � 246 Xuefu Road, Harbin, China) and informed consent was (qRT-PCR). HOTAIR forward primer: 5 -GGTAGAAAA- � � obtained from the parents or guardians. Tis study complies AGCAACCACGAAGC-3 , reverse primer: 5 -ACATAA- � with the Declaration of Helsinki. ACCTCTGTCTGTGAGTGCC-3 ,productlengthis170bp. � Reference GAPDH forward primer: 5 -CCGGGAAACTGT- � � 2.2. Defnition of Pulmonary Arterial Hypertension (PAH). GGCGTGATGG-3 , reverse primer: 5 -AGGTGGAGG- � PAH is evaluated according to the pulmonary artery systolic AGTGGGTGTCGCTGTT-3 , product length is 309 bp [13]. pressure (PASP) [10]: no pulmonary hypertension: PASP < According to the manufacturer’s protocol of the reverse 30 mmHg; pulmonary hypertension: PASP > 30 mmHg. transcription reagent kit (Bioneer company), 15 �ltotal plasma RNA was used for cDNA synthesis. Next, we used 2.3. Dividing Standard of Defect Size (DS). Defect size is the AccuPower5 2×Greenstar6 qPCR Master Mix kit (Bioneer maximum value of each section. According to the ultrasonic company) to detecte cDNA by CFX96TM real-time quanti- measurement DS defne [11, 12], for adult, small defect of tative PCR detect system (Bio-Rad company). Te reaction VSDissmallerthan1cmindiameter,smalldefectofASD was performed in 20 �lvolumewith10�l2×Greenstar Master is smaller than 2 cm in diameter, medium to large defect of Mix, 0.4 �lRoxdye,0.5�leachofforwardandreverse VSD is 1 cm or more in diameter, and medium to large defect primers, 7.2 �l DEPC-treated water, and 2.0 �lcDNA(2.0�l of ASD is 2 cm or more in diameter. For child, small defect of cDNA was replaced with 2.0 �l DEPC-treated water in nega- 2 ∘ VSDissmallerthan1cm/m in diameter, small defect of ASD tive controls). Cycling parameters were as follows: 95 Cfor10 2 ∘ is smaller than 2 cm/m in diameter, medium to large defect minutes for initial denaturation followed by 40 cycles of 95 C 2 ∘ of VSD is 1 cm/m or more in diameter, and medium to large for 15 sec and 61 Cfor1minute,thenfuorescencesignals 2 defect of ASD is 2 cm/m or more in diameter (defect size and were detected. Te Ct value was defned as the cycle number the ratio of surface area). at which the fuorescence (ΔRn) exceeded the threshold. A threshold of 0.20 was used as the default setting. Each 2.4. Tissue and Plasma Samples. Cardiac tissue specimens sample’s experiment was replicated 3 times; the average of the were acquired from right atrial appendage tissues of patients 3 results was the experimental result. Te relative expression with CHDs and patients with RVHDs during surgical resec- of target lncRNAs was determined by using the comparative −ΔΔCT tion. Ten the cardiac tissues were snap-frozen in liquid cycle threshold (Ct) method (2 ); the melt curve analysis ∘ nitrogen and stored at −80 C immediately. Blood samples was used to confrm the specifcity of amplifcation and the were collected from CHDs patients and healthy individuals absence of primer dimers. and put into a test tube containing EDTA.
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