The long noncoding RNA CARDINAL attenuates cardiac hypertrophy by modulating protein translation
Xin He, … , Da-Zhi Wang, Zhan-Peng Huang
Xin He, … , Da-Zhi Wang, Zhan-Peng Huang
Published May 14, 2024
Citation Information: J Clin Invest. 2024;134(13):e169112. https://doi.org/10.1172/JCI169112.
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Research Article Cardiology Development

The long noncoding RNA CARDINAL attenuates cardiac hypertrophy by modulating protein translation

Abstract

One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means of treating cardiac hypertrophy, although system-wide side effects are common. Regulators of translation, such as cardiac-specific long noncoding RNAs (lncRNAs), could provide new, more targeted therapeutic approaches to inhibit cardiac hypertrophy. Therefore, we generated mice lacking a previously identified lncRNA named CARDINAL to examine its cardiac function. We demonstrate that CARDINAL is a cardiac-specific, ribosome-associated lncRNA and show that its expression was induced in the heart upon pathological cardiac hypertrophy and that its deletion in mice exacerbated stress-induced cardiac hypertrophy and augmented protein translation. In contrast, overexpression of CARDINAL attenuated cardiac hypertrophy in vivo and in vitro and suppressed hypertrophy-induced protein translation. Mechanistically, CARDINAL interacted with developmentally regulated GTP-binding protein 1 (DRG1) and blocked its interaction with DRG family regulatory protein 1 (DFRP1); as a result, DRG1 was downregulated, thereby modulating the rate of protein translation in the heart in response to stress. This study provides evidence for the therapeutic potential of targeting cardiac-specific lncRNAs to suppress disease-induced translational changes and to treat cardiac hypertrophy and heart failure.

Authors

Xin He, Tiqun Yang, Yao Wei Lu, Gengze Wu, Gang Dai, Qing Ma, Mingming Zhang, Huimin Zhou, Tianxin Long, Youchen Yan, Zhuomin Liang, Chen Liu, William T. Pu, Yugang Dong, Jingsong Ou, Hong Chen, John D. Mably, Jiangui He, Da-Zhi Wang, Zhan-Peng Huang

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Figure 4

Pressure overload increases cardiac hypertrophy and enhances protein translation in Cardinal-KO mice.

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Pressure overload increases cardiac hypertrophy and enhances protein tra...
(A) Relative Cardinal expression levels detected by RT-qPCR (n ≥3 for each group) and (B) ventricular weight/body weight ratio (n ≥6 for each group). (C) H&E staining, (D) wheat germ agglutinin (WGA) staining (scale bars: 60 μm), (E) relative cardiomyocyte area quantification (n ≥6 for each group), (F) Picrosirius red/Fast Green staining (scale bars: 1 mm and 200 μm), (G) relative fibrosis area quantification (n ≥10 for each group) performed on cross sections, (H) relative expression levels of hypertrophy and fibrosis markers detected by RT-qPCR (n ≥4 for each group), and (I) echocardiographic parameters (n ≥6 for each group) of hearts from control and Cardinal-KO mice 4 weeks after sham or TAC surgery. (J) Western blot analysis and (K) quantification of puromycin-incorporated protein in hearts from control and Cardinal-KO mice 2 weeks after TAC surgery (n = 6 for each group). Mice were peritoneally injected with 25 mg/kg puromycin 45 minutes before sacrifice. (L) Western blot and (M) quantification of puromycin-incorporated protein in adult mouse cardiomyocytes from control or Cardinal-KO mice treated in culture medium with or without PE (50 μM) for 24 hours. Cells were treated with 1 μM puromycin for 30 minutes before harvesting (n = 4 for each group). (N) Summary of the GSEA results. Proteomic changes in hearts from KO TAC versus Ctrl TAC by GSEA using the gene sets from the Gene Ontology Biological Process. (O) Enrichment plot of the gene set “actin filament organization” generated by GSEA with translatomic alterations in hearts from KO TAC versus Ctrl TAC mice. (P) Heatmap showing proteomic changes in the “actin filament organization” gene set in hearts from KO TAC versus Ctrl TAC mice. Documented prohypertrophic factors among upregulated proteins are highlighted. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Student’s t test (G and K) or 2-way ANOVA with Tukey’s post hoc test (A, B, E, H, I, and M).