miRNA Expression Profile and Effect of Wenxin Granule in Rats with Ligation-Induced Myocardial Infarction

Abstract

Wenxin Granule (WXKL) is a traditional Chinese medicine used for treatment of myocardial infarction (MI) and arrhythmias. However, the genomic pathological mechanisms of MI and mechanisms of WXKL are largely unknown. This study aims to investigate a comprehensive miRNA expression profile, and the predicted correlation pathways to be targeted by differentially expressed miRNAs in MI, and mechanisms of WXKL from a gene level. MI rat model was established by a coronary artery ligation surgery. miRNA expression microarrays were performed and the data were deposited in Gene Expression Omnibus (GEO number GSE95855). And, pathway analysis was performed by using the DIANA-miRPath v3.0 online tool. The expressions of miR-1, miR-133, Cx43, and Cx45 were detected by quantitative real-time PCR. It was found that 35 differentially expressed miRNAs and 23 predicted pathways, including miR-1, miR-133, and gap junction pathway, are involved in the pathogenesis of MI. And, WXKL increased the expressions of miR-1 and miR-133, while also increased the mRNA levels of Cx43 and Cx45, and, especially, recovered the Cx43/Cx45 ratio near to normal level. The results suggest that regulatory effects on miR-1, miR-133, Cx43, and Cx45 might be a possible mechanism of WXKL in the treatment of MI at the gene level.

Therapeutic Effects of Wenxin Keli in Cardiovascular Diseases: An Experimental and Mechanism Overview

“…In the normal adult heart, there exists three main isoforms: Connexin 40 (Cx40), Connexin 43 (Cx43), and Connexin 45 (Cx45), Cx43 is the most abundant and is expressed in atrial and ventricular myocytes ( Severs et al, 2008 ). Previous studies exhibited that Cx43 expression is down-regulated when cardiac hypertrophy occurs ( Yang et al, 2012 ; Wu et al, 2017a , c ; Long et al, 2017 ), further leading to arrhythmia. WXKL protected the ultrastructure of the gap junctions and raised the phosphorylated Cx43 (Cx43-p)/non-phosphorylated Cx43 (Cx43-np) ratio ( Wu et al, 2017a , c ) and Cx43 mRNA ( Yang et al, 2012 ; Long et al, 2017 ).…”

“…Previous studies exhibited that Cx43 expression is down-regulated when cardiac hypertrophy occurs ( Yang et al, 2012 ; Wu et al, 2017a , c ; Long et al, 2017 ), further leading to arrhythmia. WXKL protected the ultrastructure of the gap junctions and raised the phosphorylated Cx43 (Cx43-p)/non-phosphorylated Cx43 (Cx43-np) ratio ( Wu et al, 2017a , c ) and Cx43 mRNA ( Yang et al, 2012 ; Long et al, 2017 ). Besides, WXKL enabled to significantly enhance the VF threshold (VFT) and reduced Q-T dispersion ( Long et al, 2017 ; Wu et al, 2017a ) to suppress arrhythmia.…”

“…In addition, there was a large number of myocardial apoptotic nuclei and the apoptosis rates were significantly increased after the coronary artery occlusion surgery. WXKL effectively restored the LVEF and left ventricular fractional shortening (LVFS), improved left ventricular end-diastolic dimension (LViDd) and left ventricular end-systolic dimension (LViDs), reduced MI size and apoptosis rate ( Zeng et al, 2006 ; Liu et al, 2012 ; Guo et al, 2013 ; Wu et al, 2013 , 2017a , b ; Xing et al, 2013 ; Wang and Liu, 2014 ; Zheng et al, 2016 ; Jiang et al, 2017 ). And WXKL also could downregulate genes associated with apoptosis, such as cathepsin C (CTSC), tetratricopeptide repeat domain 5 (TTC5), and upregulated angiogenesis promoting genes such as R-spondin 3 (RSPO3) ( Zheng et al, 2016 ).…”

“…WXKL protected the ultrastructure of the gap junctions and raised the phosphorylated Cx43 (Cx43-p)/non-phosphorylated Cx43 (Cx43-np) ratio ( Wu et al, 2017a , c ) and Cx43 mRNA ( Yang et al, 2012 ; Long et al, 2017 ). Besides, WXKL enabled to significantly enhance the VF threshold (VFT) and reduced Q-T dispersion ( Long et al, 2017 ; Wu et al, 2017a ) to suppress arrhythmia. At the level of single cardiomyocytes, hypertrophy is simply defined as an increase in the cardiomyocyte size.…”

“…Around 40–50% of all cardiovascular deaths are sudden cardiac deaths, while approximately 80% of these are caused by ventricular tachyarrhythmias ( Mehra, 2007 ). In addition, cardiac arrhythmia is also caused by cardiovascular organic lesions, such as myocardial ischemia, fibrosis, cardiac hypertrophy, impaired cardiac function and so forth, which further influence electrophysiological activity by changing the structure of the heart ( Nguyen et al, 2017 ; Wu et al, 2017a ). Traditional Chinese medicine (TCM) has more than 2,000 years of history and has gained widespread clinical applications in patients with CVDs for thousands of years and is still being commonly used in modern times in both China and elsewhere worldwide ( Hao et al, 2017 ).…”