FTO improves myocardial fibrosis by reducing m6A modification of DKK2 and promoting DKK2 expression
- VernacularTitle:FTO减少DKK2的m6A修饰和促进DKK2表达而减少心肌纤维化
- Author:
Xi LI
1
;
Kunrong WANG
2
Author Information
- Publication Type:Journal Article
- Keywords: acute myocardial infarction; myocardial fibrosis; fat mass and obesity-associated protein (FTO); m6A; DKK2
- From: Journal of Xi'an Jiaotong University(Medical Sciences) 2022;43(6):807-813
- CountryChina
- Language:Chinese
- Abstract: 【Objective】 To explore the relationship of fat mass and obesity-associated protein (FTO) with the m6A modification and expression level of DKK2 in the process of myocardial fibrosis. 【Methods】 Cardiac fibroblasts (CFs) were grouped as follows: Control group, AngⅡ-treated group, AngⅡ+EV group (transfected with empty vector and negative control siRNA and then treated with AngⅡ), AngⅡ+FTO-O group (transfected with FTO overexpression vector and then treated with AngⅡ), and AngⅡ+FTO-O+DKK2 siRNA group (treated with AngⅡ after co-transfection of FTO overexpression vector and DKK2 siRNA). Mice were divided into the following groups: Control group (sham operation group), AMI group (constructing acute myocardial infarction model), AMI+EV group (AMI mice were intraperitoneally injected with nanoparticles containing empty vector), and AMI+FTO-O group (AMI mice were intraperitoneally injected with nanoparticles containing FTO overexpression vector). Then, the expressions of FTO and DKK2 were detected by fluorescence quantitative PCR and Western blotting, the m6A modification level of DKK2 was detected by RNA binding protein immunoprecipitation, the cell viability was detected by CCK-8, the cardiac function of AMI mice was evaluated, and the cardiac pathological changes of mice were detected by HE and Masson staining. 【Results】 AngⅡ inhibited the expression of FTO, thereby enhancing the m6A modification level of DKK2 and downregulating the expression of DKK2 (P<0.05). AngⅡ promoted cell viability and enhanced the expressions of α-SMA, collagen Ⅰ and collagen Ⅲ (P<0.05). FTO overexpression significantly blocked the above-mentioned regulatory effects of AngⅡ (P<0.05), but DKK2 siRNA could antagonize the effect of FTO overexpression on AngⅡ. The expressions of FTO and DKK2 were downregulated in AMI mice, and the m6A modification level of DKK2 was increased (P<0.05). When FTO was overexpressed, the expressions of FTO and DKK2 in AMI mice were significantly restored, the m6A modification level of DKK2 and myocardial fibrosis were significantly reduced (P<0.05), and the cardiac pathological changes were significantly improved. 【Conclusion】 FTO can promote the expression of DKK2 by reducing the m6A modification level of DKK2, thereby inhibiting the progression of myocardial fibrosis. This indicates that FTO/DKK2 pathway is a key pathway in regulating myocardial fibrosis.
