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Cardiac fibrosis is characterized by the activation of cardiac fibroblasts and accumulation of extracellular matrix. METTL3, a component of methyltransferase complex, participates in multiple biological processes associated with mammalian development and disease progression. However, the role of METTL3 in cardiac fibrosis is still unknown. We performed fibroblasts activation with TGF-β1 (20 ng/mL) in vitro and established in vivo mouse models with lentivirus to assess the effects of METTL3 on cardiac fibroblasts proliferation and collagen formation. Methylated RNA immunoprecipitation (MeRIP) was used to define the potential fibrosis-regulated gene. The expression level of METTL3 was increased in cardiac fibrotic tissue of mice with chronic myocardial infarction and cultured cardiac fibroblats (CFs) treated with TGF-β1. Enforced expression of METTL3 promoted proliferation and fibroblastto-myofibroblast transition and collagens accumulation, while silence of METTL3 did the opposite. Silence of METTL3 by lentivirus carrying METTL3 siRNA markedly alleviated cardiac fibrosis in MI mice. Transcriptome and N6-methyladenosine (m 6 A) profiling analyses revealed that the expression and m 6 A level of collagen-related genes were altered after silence of METTL3. METTL3-mediated m 6 A modification is critical for the development of cardiac fibrosis, providing a molecular target for manipulating fibrosis and the associated cardiac diseases.

Background: This study aims to investigate the relationship between serum uric acid (SUA) and the severity of diabetic nephropathy (DN) and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods: A total of 2961 patients were enrolled in the present cross-sectional study. The severity of DN was determined by 24-hour urinary albumin excretion (UAE), which was classified as normal (UAE <30 mg/24 h), microalbuminuria (UAE: 30-299 mg/24 h), and macroalbuminuria (≥300 mg/24 h). The severity of DR was determined by non–mydriatic retinal photography and was classified as non–diabetic retinopathy (NDR), non–proliferative diabetic retinopathy (NPDR), and proliferative DR (PDR). Results: Patients with high SUA levels (≥420 μmol/L for males and ≥360 μmol/L for females) had a significantly higher prevalence of DN (UAE ≥30 mg/24 h, 39.3% vs 26.3%; p < 0.001), higher UAE levels (140 ± 297 vs 63 ± 175 mg/24 h; p < 0.001), and lower estimated glomerular filtration rate (eGFR; 79.3 ± 26.8 vs 96.8 ± 19.6 mL/min/1.73 m2; p < 0.001), when compared with patients with normal SUA levels. However, the prevalence of DR, NPDR, or PDR did not differ. Furthermore, the concentration of SUA was higher in patients with higher severity of DN (all, p < 0.001) and patients with PDR (compared with NDR or NPDR, p < 0.05). SUA levels were positively associated with male gender, body mass index, the use of diuretics, triglyceride, low-density lipoprotein, and UAE levels, whereas they were negatively correlated with high-density lipoprotein, fasting blood glucose, glycosylated hemoglobin, and eGFR. After adjustment, SUA remained significantly associated with UAE (r = 0.069, p < 0.001). Conclusion: For patients with T2DM, higher SUA levels are associated with higher UAE, lower eGFR, and higher prevalence of DN, but not DR.

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Purpose: Cardiomyocyte senescence is associated with a progressive decline in cardiac physiological function and the risk of cardiovascular events. lncRNA H19 (H19), a well-known long noncoding RNA (lncRNA), is involved in the pathophysiological process of multiple cardiovascular disease such as heart failure, cardiac ischemia and fibrosis. However, the role of H19 in cardiomyocyte senescence remains to be further explored.Methods: Senescence-associated β-galactosidases (SA-β-gal) staining was used to detect cardiomyocyte senescence. Western blot, qRT-PCR and luciferase reporter assay were employed to evaluate the role of H19 in cardiomyocyte senescence and its underling molecular mechanism.Results: H19 level was significantly increased in high glucose-induced senescence cardiomyocytes and aged mouse hearts. Overexpression of H19 enhanced the number of SA-β-gal-positive cells, and the expression of senescence-related proteins p53 and p21, whereas H19 knockdown exerted the opposite effects. Mechanistically, H19 was demonstrated as a competing endogenous RNA (ceRNA) for microRNA-19a (miR-19a): H19 overexpression downregulated miR-19a level, while H19 knockdown upregulated miR-19a. The expression of SOSC1 was dramatically increased in senescence cardiomyocytes and aged mouse hearts. Further experiments identified SOCS1 as a downstream target of miR-19a. H19 upregulated SOCS1 expression and activated the p53/p21 pathway by targeting miR-19a, thus promoting the cardiomyocytes senescence.Conclusion: Our results show that H19 is a pro-senescence lncRNA in cardiomyocytes acting as a ceRNA to target the miR-19a/SOCS1/p53/p21 pathway. Our research reveals a molecular mechanism of cardiomyocyte senescence regulation and provides a novel target of the therapy for senescence-associated cardiac diseases.