m<sup>6</sup>A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

doi:10.1007/s11684-023-1052-4

Front. Med.

2024, Vol. 18

Issue (3) : 499-515 https://doi.org/10.1007/s11684-023-1052-4

m⁶A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation

Han Wu, Weitao Jiang, Ping Pang, Wei Si, Xue Kong, Xinyue Zhang, Yuting Xiong, Chunlei Wang, Feng Zhang, Jinglun Song, Yang Yang, Linghua Zeng, Kuiwu Liu, Yingqiong Jia, Zhuo Wang, Jiaming Ju, Hongtao Diao(

), Yu Bian(

), Baofeng Yang(

)

Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China

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Abstract

Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N⁶-methyladenosine (m⁶A) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the m⁶A reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-β (TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.

Keywords cardiac fibrosis YTHDF1 AXL ZBED6 heart failure

Corresponding Author(s): Hongtao Diao,Yu Bian,Baofeng Yang

Just Accepted Date: 29 February 2024 Online First Date: 24 May 2024 Issue Date: 17 June 2024

Cite this article:

Han Wu,Weitao Jiang,Ping Pang, et al. m⁶A reader YTHDF1 promotes cardiac fibrosis by enhancing AXL translation[J]. Front. Med., 2024, 18(3): 499-515.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1052-4
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I3/499

Fig.1 Changes in YTHDF1 expression after MI surgery for 4 weeks and TGF-β treatment. (A) YTHDF1 mRNA levels in mouse hearts. n = 6. **P < 0.01 vs. Sham. (B) Representative image of Western blot and quantitative analysis of YTHDF1 protein expression in mouse hearts. n = 5. *P < 0.05 vs. Sham. (C) mRNA expression level of YTHDF1 in TGF-β-treated CFs obtained from neonatal mice. n = 5. *P < 0.05 vs. Ctrl. (D) YTHDF1 protein expression level in CFs obtained from neonatal mice activated by TGF-β. n = 5. **P < 0.01 vs. Ctrl. (E) Representative diagram of YTHDF1 expression in CFs obtained from neonatal mice. Scale bar = 20 μm. n = 5. **P < 0.01 vs. Ctrl.

Fig.2 Inhibition of YTHDF1 reverses MI-induced cardiac fibrosis in mice. (A) YTHDF1 knockdown efficiency determination in mouse heart tissue after delivering shRNA-YTHDF1 AAV9 via tail vein. n = 6. **P < 0.01 vs. shNC-V. (B) Protein expression level of YTHDF1 was measured in each group. n = 4. **P < 0.01 vs. Sham + shNC-V; ^##P < 0.01 vs. MI + shNC-V. (C) Echocardiography images and quantitative statistics. (D) EF (%), (E) FS (%), (F) LVID;d (mm), and (G) LVID;s (mm). n = 7. **P < 0.01 vs. Sham + shNC-V; ^#P < 0.05, ^##P < 0.01 vs. MI + shNC-V. (H, I) The areas of fibrosis in the infarcted hearts were assessed using Masson staining. Scale bar = 1 mm. n = 4. **P < 0.01 vs. Sham + shNC-V; ^##P < 0.01 vs. MI + shNC-V. (J) The heart-to-body weight ratio. n = 7. **P < 0.01 vs. Sham + shNC-V; ^#P < 0.05 vs. MI + shNC-V. (K, L) Immunofluorescence assay of α-SMA in mouse hearts. Scale bar = 20 μm. n = 4. **P < 0.01 vs. Sham + shNC-V; ^##P < 0.01 vs. MI + shNC-V. (M) qRT-PCR analysis of fibrosis marker in mouse hearts. n = 4–5. **P < 0.01 vs. Sham + shNC-V; ^##P < 0.01 vs. MI + shNC-V.

Fig.3 Overexpression of YTHDF1 exacerbates cardiac fibrosis induced by MI injury. (A) YTHDF1 overexpression efficiency determination in mouse hearts after delivering AAV9 vector via tail vein. n = 4. **P < 0.01 vs. NC-V. (B) YTHDF1 protein expression level was measured in each group. n = 4. **P < 0.01 vs. Sham + NC-V; ^##P < 0.01 vs. MI + NC-V. (C) Representative images of echocardiographs and statistics. (D) EF (%), (E) FS (%), (F) LVID;d (mm), and (G) LVID;s (mm). n = 5. *P < 0.05, **P < 0.01 vs. Sham + NC-V; ^#P < 0.05, ^##P < 0.01 vs. MI + NC-V. (H) The heart-to-body weight ratio in YTHDF1-overexpressed mice post-MI injury. n = 5. *P < 0.05 vs. Sham + NC-V; ^#P < 0.05 vs. MI + NC-V. (I, J) Masson staining of heart sections showing the fibrosis areas. Scale bar = 1 mm. n = 4. **P < 0.01 vs. Sham + NC-V; ^#P < 0.05 vs. MI + NC-V. (K, L) Representative images and quantification of immunofluorescence analysis of α-SMA in mouse hearts. Scale bar = 20 μm. n = 4. **P < 0.01 vs. Sham + NC-V; ^##P < 0.01 vs. MI + NC-V. (M) The mRNA expression levels of fibrotic genes in mice. n = 4–6. *P < 0.05, **P < 0.01 vs. Sham + NC-V; ^#P < 0.05, ^##P < 0.01 vs. MI + NC-V.

Fig.4 Suppression of YTHDF1 prevents TGF-β-induced CFs obtained from neonatal mice activation in vitro. (A, B) qRT-PCR and Western blot analysis of si-YTHDF1 transfection efficiency. n = 5. **P < 0.01 vs. si-NC. (C) The YTHDF1 protein expression level was detected by Western blot in each group. n = 5. **P < 0.01 vs. si-NC; ^##P < 0.01 vs. TGF-β + si-YTHDF1. (D) CCK-8 detected cell viability in CFs obtained from neonatal mice. n = 6. **P < 0.01 vs. si-NC; ^##P < 0.01 vs. TGF-β + si-NC. (E, F) EdU staining measured CFs obtained from the proliferation of neonatal mice. n = 4. **P < 0.01 vs. si-NC; ^##P < 0.01 vs. TGF-β + si-NC. (G, H) The migration ratio in each group. Scale bar = 100 μm. n = 5. **P < 0.01 vs. si-NC; ^##P < 0.01 vs. TGF-β + si-NC. (I, J) Fluorescence intensity of α-SMA in CFs obtained from neonatal mice determined by immunofluorescence. Scale bar = 20 μm. n = 4. **P < 0.01 vs. si-NC; ^##P < 0.01 vs. TGF-β + si-NC. (K) mRNA expression levels of fibrosis-related genes. n = 4–6. *P < 0.05, **P < 0.01 vs. si-NC; ^#P < 0.05, ^##P < 0.01 vs. TGF-β + si-NC.

Fig.5 ZBED6 regulated YTHDF1 expression. (A–C) ZBED6 mRNA and protein expression in mice with MI. n = 5–6. **P < 0.01 vs. Sham. (D–F) Expression levels of ZBED6 in TGF-β-activated CFs obtained from neonatal mice. n = 7. **P < 0.01 vs. Ctrl. (G–I) Si-ZBED6 transfection efficiency. n = 5–6. **P < 0.01 vs. si-NC. (J–L) YTHDF1 expression level post-transfected with si-ZBED6. n = 4–5. **P < 0.01 vs. si-NC. (M–O) Overexpression efficiency of ZBED6. n = 5–6. **P < 0.01 vs. NC. (P–R) YTHDF1 expression level after ZBED6 overexpression. n = 4–6. **P < 0.01 vs. NC. (S) Relative activity of luciferase. n = 3. **P < 0.01 vs. NC. (T) The binding of ZBED6 to the YTHDF1 promoter was analyzed by ChIP-qPCR. n = 3. **P < 0.01 vs. IgG. (U) EMSA using nuclear extracts from CFs obtained from neonatal mice and the indicated probes.

Fig.6 YTHDF1 activates TGF-β/Smad signaling by promoting AXL translation. (A–C) Representative image of the Western blot results of AXL. n = 5–6. *P < 0.05, **P < 0.01 vs. Sham + shNC-V, Sham + NC-V, si-NC; ^#P < 0.05, ^##P < 0.01 vs. MI + shNC-V, MI + NC-V, TGF-β + si-NC. (D, E) Expression of AXL in CFs obtained from neonatal mice determined by immunofluorescence. Scale bar = 20 μm. n = 4. **P < 0.01 vs. si-NC; ^##P < 0.01 vs. TGF-β + si-NC. (F) AXL protein expression level post-YTHDF1-AdV treatment in CFs obtained from neonatal mice. n = 4. *P < 0.05 vs. NC-AdV. (G, H) Immunofluorescence determined AXL expression in CFs obtained from neonatal mice. Scale bar = 20 μm. n = 4. **P < 0.01 vs. NC-AdV. (I) m⁶A qRT-PCR validation of m⁶A levels in sham mouse hearts. n = 5. *P < 0.05 vs. IgG. (J) YTHDF1 RIP succedent by qRT-PCR proved the interaction of YTHDF1 and AXL mRNA. n = 3. **P < 0.01 vs. IgG. (K and L) Western blot analysis of AXL protein expression upon CHX treatment after transfection with si-YTHDF1 or YTHDF1-AdV in CFs obtained from neonatal mice. n = 5–6. *P < 0.05 vs. si-NC, NC-AdV CHX = 0 h; ^#P < 0.05 vs. si-NC, NC-AdV CHX = 3 h. (M) The protein expression level of TGF-β1 and phosphorylated Smad2/3 to total Smad2/3 ratio were detected by Western blot in mice. n = 5. **P < 0.01 vs. Sham + shNC-V; ^#P < 0.05 vs. MI + shNC-V. (N) TGF-β1 expression level and phosphorylated Smad2/3 to total Smad2/3 ratio in CFs obtained from neonatal mice were measured in each group. n = 5–6. *P < 0.05 vs. si-NC; ^#P < 0.05 vs. TGF-β + si-NC.

Fig.7 YTHDF1 stimulates cardiac fibrosis by targeting AXL in vitro. (A) Overexpression efficiency of YTHDF1-AdV. n = 6. **P < 0.01 vs. NC-AdV. (B) si-AXL transfection efficiency in CFs obtained from neonatal mice. n = 5. **P < 0.01 vs. si-NC. (C) Viability of CCK-8-detected CFs obtained from neonatal mice. n = 6. **P < 0.01 vs. NC-AdV; ^##P < 0.01 vs. YTHDF1-AdV. (D, E) CFs obtained from the migration ratio of neonatal mice in each group. Scale bar = 100 μm. n = 4. **P < 0.01 vs. NC-AdV; ^##P < 0.01 vs. YTHDF1-AdV. (F, G) EdU assay of CFs obtained from the proliferation of neonatal mice. n = 4. **P < 0.01 vs. NC-AdV; ^##P < 0.01 vs. YTHDF1-AdV. (H, I) α-SMA representative immunofluorescence diagram. Scale bar = 20 μm. n = 4. **P < 0.01 vs. NC-AdV; ^##P < 0.01 vs. YTHDF1-AdV. (J) mRNA expression levels of fibrotic genes in CFs obtained from neonatal mice. n = 4–5. *P < 0.05, **P < 0.01 vs. NC-AdV; ^##P < 0.01 vs. YTHDF1-AdV. (K) TGF-β1 protein expression and phosphorylated Smad2/3 to total Smad2/3 ratio in CFs obtained from neonatal mice. n = 4–5. *P < 0.05, **P < 0.01 vs. NC-AdV; ^#P < 0.05 vs. YTHDF1-AdV.

Fig.8 The transcriptional repressor ZBED6 decreased the expression level of YTHDF1, which recognizes AXL methylation sites and promotes the overall mRNA translation of AXL, thereby resulting in TGF-β/Smad2/3 signaling pathway activation and myocardial fibrosis aggravation, furnishing a novel therapeutic value to clinical cardiovascular disease.

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