Changes in N6-Methyladenosine Modification Modulate Diabetic Cardiomyopathy by Reducing Myocardial Fibrosis and Myocyte Hypertrophy.

Wenhao Ju,Feng He,Shengrong Ouyang,Kai Liu,Zhuo Liu,Jianxin Wu

doi:10.3389/fcell.2021.702579

Abstract

In this study, we aimed to systematically profile global RNA N6-methyladenosine (m6A) modification patterns in a mouse model of diabetic cardiomyopathy (DCM). Patterns of m6A in DCM and normal hearts were analyzed via m6A-specific methylated RNA immunoprecipitation followed by high-throughput sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). m6A-related mRNAs were validated by quantitative real-time PCR analysis of input and m6A immunoprecipitated RNA samples from DCM and normal hearts. A total of 973 new m6A peaks were detected in DCM samples and 984 differentially methylated sites were selected for further study, including 295 hypermethylated and 689 hypomethylated m6A sites (fold change (FC) > 1.5, P < 0.05). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway analyses indicated that unique m6A-modified transcripts in DCM were closely linked to cardiac fibrosis, myocardial hypertrophy, and myocardial energy metabolism. Total m6A levels were higher in DCM, while levels of the fat mass and obesity-associated (FTO) protein were downregulated. Overexpression of FTO in DCM model mice improved cardiac function by reducing myocardial fibrosis and myocyte hypertrophy. Overall, m6A modification patterns were altered in DCM, and modification of epitranscriptomic processes, such as m6A, is a potentially interesting therapeutic approach.

Highlights

There are more than 450 million patients with diabetes worldwide, and by 2045 this number is predicted to increase to 693 million (Cho et al, 2018)
Mice with diabetic cardiomyopathy (DCM) showed a significantly decreased E to A wave ratio (E/A) compared with the normal control (NC) group (n = 5, P < 0.0001; Figures 1J,K), indicating that the diastolic function of the heart was abnormal in DCM mice
Blood glucose (BG), triglyceride (TG), and total cholesterol (TC) were significantly increased in db/db (DCM) mice at 16 weeks compared with db/ + mice (Supplementary Figure 1), indicating that db/db mice had abnormal blood glucose and lipid metabolism

Summary

Introduction

There are more than 450 million patients with diabetes worldwide, and by 2045 this number is predicted to increase to 693 million (Cho et al, 2018). Cardiovascular disease accounts for 50.3% of total deaths of patients with diabetes (Einarson et al, 2018). Diabetes increases the risk of heart failure, and increases the mortality rate from heart failure by 2.5 times (Tan et al, 2020). Diabetic cardiomyopathy (DCM) is a metabolic cardiovascular disease m6A Methylation in Diabetic Cardiomyopathy resulting in decreased myocardial glucose consumption, modestly increased ketone metabolism, and significantly increased utilization of fatty acids (Ritchie and Abel, 2020; Tan et al, 2020). The main features of DCM are myocardial hypertrophy, cardiac fibrosis, coronary microvascular dysfunction, left ventricular enlargement, and weakened ventricular wall motion (Ritchie and Abel, 2020); the causal relationships among these complications are not clear.

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