mir‐140 and mir‐6321/miR‐6321 Contribute the Pathogenesis in Acute Myocardial Infarction Revealed by Integrative Study of mRNA and microRNA Transcriptomes
Authors: Wang Yong , Lin Weili , Nugent Colleen A. , Zhu Ruixin , Li Chun , Zhu Lixin , Wang Wei 
Published: November 2023

Background

Acute myocardial infarction (AMI) is a common cardiovascular event which results in ventricular remodelling (VR) and can consequently develop into heart failure (HF). HF induced by AMI remains one of the leading causes of morbidity and mortality worldwide. Recently, microRNA has emerged as a posttranscriptional regulator to mediate important pathophysiological processes in AMI, which induces degradation or blocks translation of target mRNA. In our study, integrative analysis of mRNA and microRNA transcriptomes provided new insights to microRNA contribution in pathogenesis of AMI.

Methods

Sprague‐Dawley (SD) rats were randomly divided into 2 groups (3 rats in each group): Sham‐operated group and AMI model group. AMI model was induced by ligation of left anterior descending coronary artery. Twenty eight days after surgery, cardiac tissue was harvested for high throughput sequencing of both mRNA and microRNA transcriptomes. Differential expression analysis (FDR<0.05 and fold change>1.5 or <0.667) and functional enrichment analysis (P value<0.05) were performed to detect deregulated mRNA and microRNA. Furthermore, microRNA target analysis and inversely correlation analysis (P value<0.05) were performed to identify negative regulation between deregulated mRNA and microRNA.

Results

Differential expression analysis of mRNA revealed that an amount of VR‐markers were significantly up‐regulated in the AMI model group, including collagens (COL2A1, COL9A1, COL11A1, COL6A5, COL9A2, COL4A3, COL13A1, COL4A6, COL18A1, COL16A1, COL12A1 and COL20A1) and integrins (IBSP, ITGA10, ITGA8, ITGA11, ITGB8 and ITGA1). Several key enzymes or regulators in fatty acid and glucose metabolism were markedly supressed in the AMI model group, including ACACB, ECI1, ACCAA2, CYP4A2, CYP4A3, RXRG, PYGB, PRKAG3 and PFKFB1. Functional enrichment analysis of mRNA showed that up‐regulated genes were mainly enriched in ECM‐receptor interaction, PI3K‐Akt signalling pathway and dilated cardiomyopathy. Meanwhile, suppressed genes were relevant to energy metabolism, including fatty acid degradation, PPAR and glucagon signalling pathway. Differential expression analysis of microRNA identified the over‐expression of mir‐140 and reduced expression of mir‐6321 and miR‐6321 in the AMI model group. Furthermore, mir‐140 was negatively correlated with the target genes of its mature forms, which were down‐regulated and involved in glucagon and PPAR signalling pathway, and fatty acid degradation. Moreover, identified target genes of miR‐6321 were significantly highly expressed in the AMI model group and related to VR, including cell adhesion molecules and collagens.

Conclusions

Our study for the first time identified mir‐140 and mir‐6321/miR‐6321 as candidate master regulators in pathogenesis of AMI. The over‐expression of mir‐140 suppressed its target genes involved in fatty acid and glucose oxidation, and thus reduced energy supply to cardiac contractility and relaxation. Meanwhile, the down‐regulation of mir‐6321/miR‐6321 led to increased expression of its target genes, which further exacerbated VR in AMI development.

Support or Funding Information

This work was financially supported, in part, by the Grants from the National Natural Science Foundation of China (No. 81302908, 81530100, 81473456, 81503379 and 81470191), Beijing Natural Science Foundation (No.7142099), Fok Ying Tung Education Foundation (No. 151044), and excellent young scientist foundation of BUCM (No.2016‐JYB‐XJ003, 2015‐JYB‐QNJSZX001 and 2015‐JYB‐XYQ001).