lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the PGC-1<strong>α</strong>–mitochondrial complex IV axis

doi:10.1007/s11684-024-1065-7

Front. Med.

2024, Vol. 18

Issue (4) : 664-677 https://doi.org/10.1007/s11684-024-1065-7

lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the PGC-1α–mitochondrial complex IV axis

Tong Yu¹, Qiang Gao², Guofang Zhang⁴, Tianyu Li⁴, Xiaoshan Liu¹, Chao Li⁴, Lan Zheng², Xiang Sun⁴, Jianbo Wu⁴, Huiying Cao⁴, Fangfang Bi⁴, Ruifeng Wang⁴, Haihai Liang⁴, Xuelian Li⁴, Yuhong Zhou⁴, Lifang Lv^2,³(

), Hongli Shan¹(

)

¹. Shanghai Frontiers Science Research Center for Druggability of Cardiovascular Noncoding RNA, Institute for Frontier Medical Technology, Shanghai University of Engineering Science, Shanghai 201620, China
². Department of Physiology, School of Basic Medicine, Harbin Medical University, Harbin 150081, China
³. The Center of Functional Experiment Teaching, School of Basic Medicine, Harbin Medical University, Harbin 150081, China
⁴. State Key Laboratory of Frigid Zone Cardiovascular Disease, Department of Pharmacology (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

Pathological cardiac hypertrophy, a major contributor to heart failure, is closely linked to mitochondrial function. The roles of long noncoding RNAs (lncRNAs), which regulate mitochondrial function, remain largely unexplored in this context. Herein, a previously unknown lncRNA, Gm20257, was identified. It markedly increased under hypertrophic stress in vivo and in vitro. The suppression of Gm20257 by using small interfering RNAs significantly induced cardiomyocyte hypertrophy. Conversely, the overexpression of Gm20257 through plasmid transfection or adeno-associated viral vector-9 mitigated angiotensin II–induced hypertrophic phenotypes in neonatal mouse ventricular cells or alleviated cardiac hypertrophy in a mouse TAC model respectively, thus restoring cardiac function. Importantly, Gm20257 restored mitochondrial complex IV level and enhanced mitochondrial function. Bioinformatics prediction showed that Gm20257 had a high binding score with peroxisome proliferator–activated receptor coactivator-1 (PGC-1α), which could increase mitochondrial complex IV. Subsequently, Western blot analysis results revealed that Gm20257 substantially affected the expression of PGC-1α. Further analyses through RNA immunoprecipitation and immunoblotting following RNA pull-down indicated that PGC-1α was a direct downstream target of Gm20257. This interaction was demonstrated to rescue the reduction of mitochondrial complex IV induced by hypertrophic stress and promote the generation of mitochondrial ATP. These findings suggest that Gm20257 improves mitochondrial function through the PGC-1α–mitochondrial complex IV axis, offering a novel approach for attenuating pathological cardiac hypertrophy.

Keywords lncRNA Gm20257 cardiac hypertrophy PGC-1α mitochondrial complex IV ATP

Corresponding Author(s): Lifang Lv,Hongli Shan

Just Accepted Date: 11 June 2024 Online First Date: 26 June 2024 Issue Date: 30 August 2024

Cite this article:

Tong Yu,Qiang Gao,Guofang Zhang, et al. lncRNA Gm20257 alleviates pathological cardiac hypertrophy by modulating the PGC-1α–mitochondrial complex IV axis[J]. Front. Med., 2024, 18(4): 664-677.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-024-1065-7
https://academic.hep.com.cn/fmd/EN/Y2024/V18/I4/664

Tab.1 Primers used for qRT-PCR analysis

Fig.1 Upregulation of lncRNA Gm20257 in mice with cardiac hypertrophy in vivo and in vitro. (A) Pressure overload cardiac hypertrophy was established in C57BL/6 mice through TAC surgery. The ratios of heart weight/body weight (HW/BW), lung weight/body weight (LW/BW), and heart weight/ tibia length (HW/TL) were detected in the TAC and sham groups (n = 6). (B) mRNA levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and β-myosin heavy chain (β-MHC) were assumed in the TAC and sham-operated mice (n = 6). (C) Level of Gm20257 in the heart of TAC or sham mice (n = 6). (D) Cardiomyocytes were incubated with Ang II for 48 h to establish cardiomyocyte hypertrophy. Representative pictures of cardiomyocytes with or without Ang II treatment are provided (n = 18; blue, DAPI; red, α-actinin. Scale bar, 20 μm). (E) mRNA levels of ANP, BNP, and β-MHC in control or Ang II-treated cardiomyocytes (n = 6). (F) Expression of Gm20257 in control or Ang II-treated cardiomyocytes (n = 5–6). (G) Subcellular localization of Gm20257 in cultured cardiomyocytes detected by FISH (DAPI indicates 4',6-diamidino-2-phenylindole and was used to stain nuclei; scale bar, 20 μm). *P < 0.05, **P < 0.01.

Fig.2 lncRNA Gm20257 inhibits cardiac hypertrophy in neonatal mouse ventricular myocytes (NMVMs). (A) Expression of Gm20257 after the transfection of its small interfering RNA (si-Gm20257) (n = 5). (B) Cardiomyocyte cross-sectional area analysis based on staining with α-actinin (n = 18; blue, DAPI; red, α-actinin. Scale bar, 20 μm). (C) mRNA expression levels of ANP, BNP, and β-MHC in cardiomyocytes transfected with si-NC or si-Gm20257 (n = 3). (D) Protein levels of β-MHC in cardiomyocytes transfected with si-NC or si-Gm20257 (n = 6). (E) Expression levels of Gm20257 after the transfection of its overexpression plasmids (n = 6). (F) Cardiomyocyte cross-sectional area detected through staining with α-actinin. Cardiomyocytes were transfected with Gm20257 overexpression plasmids or the vector control and subsequently treated with PBS or Ang II (1 µmol/L) for 48 h (n = 14–18; blue, DAPI; red, α-actinin. Scale bar, 20 μm). (G) mRNA expression levels of ANP, BNP, and β-MHC in cardiomyocytes (n = 4–6). (H) Protein level of β-MHC in cardiomyocytes (n = 6–8). *P < 0.05, **P < 0.01.

Tab.2 Echocardiographic indicators

Fig.3 Specific overexpression of lncRNA Gm20257 attenuates TAC-induced cardiac hypertrophy in mouse hearts. (A) Expression of lncRNA Gm20257 after the injection of AAV9-containing Gm20257 or vector in mice. The mice subsequently underwent sham or TAC surgery for 4 weeks (n = 4–5). (B) Ratios of heart weight/ body weight (HW/ BW), lung weight/body weight (LW/BW), and heart weight/tibia length (HW/TL) were detected in the sham or TAC mice infected with AAV9–vector or AAV9–Gm20257 (n = 4–5). (C, D) Ejection fraction (EF) and fraction shortening (FS) were evaluated by echocardiography (n = 4–5). (E) Representative echocardiography results and quantification data of left ventricular posterior wall diastole (LVPW;d) (top) (n = 4–5). TEM analysis of the ultrastructure of cardiomyocytes of the heart, including mitochondria and myofilament (middle; scale bar, 2 μm), and wheat germ agglutinin staining (bottom; scale bar, 20 μm) and corresponding group quantification data (n = 4–5). (F) mRNA expression of ANP, BNP, and β-MHC in the mouse heart (n = 4–5). (G) Protein level of β-MHC in the mouse heart (n = 4). *P < 0.05, **P < 0.01.

Fig.4 lncRNA Gm20257 promotes mitochondrial complex IV expression and ATP production. (A, B) KEGG and GO analysis of the lncRNA Gm20257 interactome demonstrated the close relationship of the ETC of oxidative phosphorylation with Gm20257. (C, D) Protein level of mitochondrial ETC (n = 4 in C; n = 7 in D). (E, H) Representative images of the JC-1 staining of mitochondria. JC-1 exhibited potential-dependent accumulation. Mitochondria have high potential in healthy cells, thus inducing JC-1 to form complexes that emit red fluorescence, but have low potential in unhealthy cells, inducing JC-1 to remain in a monomeric form, which emits green fluorescence (n = 4–6 in E; n = 9 in H; scale bar, 20 μm). (F, I) ROS levels were determined in cardiomyocytes with the ROS-specific probe DCFH-DA (n = 18–19 in F; n = 20 in I; scale bar, 20 μm in F; scale bar, 50 μm in I). (G, J) ATP content determined in cardiomyocytes (n = 6 in G; n = 5–6 in J). *P < 0.05, **P < 0.01.

Fig.5 PGC-1α is a potential downstream target of lncRNA Gm20257. (A) Heat-map of the prediction of the interaction between lncRNA Gm20257 and PGC-1α obtained by using the catRAPID database. The x- and the y-axes represent the indices of RNA and protein sequences, respectively. The colors of the heat map indicate the interaction score (ranging from 23 to 13) of individual amino acid and nucleotide pairs. The total sum represents the overall interaction score (interaction propensity = 105 and discriminative power = 99%). (B) Binding site of Gm20257 and PGC-1α identified by using the catRAPID database. The interaction profile represents the interaction score (y-axis) of the protein along the RNA sequence (x-axis), giving information about the transcript regions that are most likely to be bound by the protein. (C–G) Protein level of PGC-1α in heart tissue or cardiomyocytes (n = 4 in C; n = 6 in D; n = 4 in E; n = 5 in F; n = 6 in G). (H) Western blot analysis of PGC-1α pulled down by Gm20257. Data were reproduced in two independent experiments. (I) RNA immunoprecipitation of Gm20257 by PGC-1α antibodies. *P < 0.05, **P < 0.01.

Fig.6 PGC-1α mediates the regulatory effect of lncRNA Gm20257 on mitochondrial complex IV and mitochondrial ATP production. (A) Protein levels of PGC-1α and mitochondrial ETC (n = 6). (B) Representative images of the JC-1 staining of mitochondria (n = 13; scale bar, 50 μm). (C) ROS levels in cardiomyocytes determined with the ROS-specific probe DCFH-DA (n = 18–19; scale bar, 50 μm). (D) ATP content in cardiomyocytes (n = 5–6). (E) Cardiomyocytes were transfected with the Gm20257 overexpression plasmid or with the Gm20257 overexpression plasmid simultaneously with the small interfering RNA of PGC-1α or NC. Cardiomyocyte cross-sectional area was measured by staining with α-actinin (n = 18; blue, DAPI; red, α-actinin. Scale bar, 20 μm). (F) mRNA expression levels of ANP, BNP, and β-MHC in all groups (n = 5–6). (G) Protein levels of β-MHC and PGC-1α in all groups (n =6). *P < 0.05, **P < 0.01.

Fig.7 Diagram of the regulatory effect of lncRNA Gm20257 on pathological cardiac hypertrophy. lncRNA Gm20257 directly binds to PGC-1α, effectively preventing hypertrophic stress-induced PGC-1α reduction and subsequently increasing mitochondrial complex IV. This effect leads to increased ATP generation, which then helps inhibit pathological cardiac hypertrophy.

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