Modulation of the expression of fibrotgenesis related long non-coding RNAs by endurance exercise in the hearts of rats with myocardial infarction

Modulation of the expression of fibrotgenesis related long non-coding RNAs by endurance exercise in the hearts of rats with myocardial infarction
Saeideh Jafarinejad Farsangi,¹ Farzaneh Rostamzadeh,^2,* Mozhgan Sheikholeslami,³ Elham Jafai,⁴
1. Student Research Committee, Kerman University of Medical Sciences, Kerman, Iran
2. Physiology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
3. Cardiovascular Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran
4. Pathology and Stem Cell Research Center, Kerman University of Medical Sciences, Kerman, Iran
Introduction: Cardiovascular diseases (CVDs) are the first cause of death worldwide. Coronary artery diseases (CADs) including myocardial infarction (MI) account for about 40% of CVD-related deaths. Low physical activity is one of the important risk factors for CADs. Physical activity (PA) dramatically lowers the risk of CADs, including MI, by up to 50% . It has been shown that as a basic part of cardiac rehabilitation programs, exercise training reduces mortality and re-infarction and improves quality of life in patients suffering from CADs, especially MI and heart failure (HF). The previously assumed “junk DNA” encodes for a group of non-coding RNAs (ncRNAs) as a new layer of gene regulation. Non-coding RNAs are classified according to the length of the oligonucleotides into small (20-25 nt) (microRNA) and long (> 200 nt) (LncRNAs) ncRNAs. LncRNAs comprise about 70% of ncRNAs and their regulatory function is emerging in a wide range of genomic and cellular processes including chromatin remodeling, genomic imprinting and post/transcriptional regulation, cell differentiation and invasion. Given their abnormal expression in cardiac diseases, lncRNAs have been regarded as potential therapeutic targets for CVDs. Dysregulation of lncRNAs H19, myocardial infarction association transcript (MIAT), and growth arrest specific 5 (GAS5) has been previously reported in MI. H19 as a regulator of extracellular matrix (ECM) facilitates fibrotic procedures at early stages of cardiac remodeling after MI. MIAT has been introduced as a pro-fibrotic lncRNA in the pathogenesis of MI. MIAT expression increases in the peri-infarct area and activates cardiac fibrosis through the MIAT/miR-24/Furin axis. Inhibition of GAS5 in isoproterenol induced MI models reduced cardiomyocyte apoptosis and ameliorated subsequent cardiac fibrosis.
Methods: Left anterior descending (LAD) coronary artery ligation was used as the model for MI induction in male Wistar rats. Animals were randomly divided into 4 groups: Sham, Myocardial Infarction (MI), Sham + Exercise (EXE) and Myocardial Infarction + Exercise (MI + EXE). Each group consisted of 12 rats. Exercise training (Ex) was performed according to 5 days/week, 50 min/day at 16 m/min program for four weeks following a five-minute warm-up at 10 m/min. In the end, hemodynamic parameters and cardiac function indices were measured. Masson is trichrome staining performed assessment of fibrotic areas. Expression of genes was evaluated by real-time PCR.
Results: Masson’s trichrome staining indicated that Ex significantly reduced the fibrotic area of the hearts exposed to MI (P < 0.05). Ex normalized (P < 0.05) the increased left ventricular systolic pressure (LVSP) and heart rate in the MI group (P < 0.05). Ex returned the reduction of -dp/dt max that had accomplished during MI (P < 0.05). The expression of H19 was significantly reduced (P < 0.01) in MI group in compare with sham. We observed that the reduced expression of H19 (P < 0.01) in MI rats returned to normal levels by Ex. Ex significantly (P < 0.001) reduced the expression of MIAT and increased the expression of GAS5 (P < 0.01), which had changed in the hearts of rats with MI.
Conclusion: The present study indicated the beneficial effect of Ex on the improvement of cardiac function and reduction of fibrosis in infarcted heart possibly through regulation of the expression of lncRNAs: H19, GAS5, and MIAT.
Keywords: long non-coding RNA, exercise, myocardial infarction, H19, MIAT, GAS5