The long noncoding RNA CARDINAL attenuates cardiac hypertrophy by modulating protein translation
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
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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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 8

Proposed model for the regulation of mRNA translation and cardiac hypertrophy by CARDINAL.

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Proposed model for the regulation of mRNA translation and cardiac hypert...
(A) Cardinal is a cardiac-specific lncRNA that can suppress mRNA translation. Under normal conditions, the expression of Cardinal and the ribosome-binding protein DRG1 (which promotes mRNA translation) are in balance. We propose that CARDINAL inhibits mRNA translation by interference with DRG1 function. CARDINAL binds DRG1 and interferes with the formation of the DRG1-DFRP1 stabilization complex; inhibition of DRG1-DFRP1 complex formation by CARDINAL results in reduced levels of DRG1, which helps maintain a normal level of translation. (B) Under stress conditions, both the lncRNA CARDINAL and DRG1 are upregulated. However, while Cardinal attempts to inhibit cardiomyocyte translation, it is no longer able to balance the increased translation induced by the increase in DRG1; the result is a net increase in mRNA translation and cardiac hypertrophy. (C) In the absence of CARDINAL, the constraint on DRG1 levels is lost. The result is an even greater elevation of protein synthesis and worsening of cardiac hypertrophy.