Shanghai Frontiers Science Research Center for Druggability of Cardiovascular noncoding RNA, Institute for Frontier Medical Technology, Shanghai University of Engineering Science, Shanghai, 201620, China.
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.
Cell Death Dis. 2023 May 30;14(5):344. doi: 10.1038/s41419-023-05852-7.
Cardiac hypertrophy is a common structural remodeling in many cardiovascular diseases. Recently, long non-coding RNAs (LncRNAs) were found to be involved in the physiological and pathological processes of cardiac hypertrophy. In this study, we found that LncRNA KCND1 (LncKCND1) was downregulated in both transverse aortic constriction (TAC)-induced hypertrophic mouse hearts and Angiotensin II (Ang II)-induced neonatal mouse cardiomyocytes. Further analyses showed that the knockdown of LncKCND1 impaired cardiac mitochondrial function and led to hypertrophic changes in cardiomyocytes. In contrast, overexpression of LncKCND1 inhibited Ang II-induced cardiomyocyte hypertrophic changes. Importantly, enhanced expression of LncKCND1 protected the heart from TAC-induced pathological cardiac hypertrophy and improved heart function in TAC mice. Subsequent analyses involving mass spectrometry and RNA immunoprecipitation assays showed that LncKCND1 directly binds to YBX1. Furthermore, overexpression of LncKCND1 upregulated the expression level of YBX1, while silencing LncKCND1 had the opposite effect. Furthermore, YBX1 was downregulated during cardiac hypertrophy, whereas overexpression of YBX1 inhibited Ang II-induced cardiomyocyte hypertrophy. Moreover, silencing YBX1 reversed the effect of LncKCND1 on cardiomyocyte mitochondrial function and its protective role in cardiac hypertrophy, suggesting that YBX1 is a downstream target of LncKCND1 in regulating cardiac hypertrophy. In conclusion, our study provides mechanistic insights into the functioning of LncKCND1 and supports LncKCND1 as a potential therapeutic target for pathological cardiac hypertrophy.
心肌肥厚是许多心血管疾病中常见的结构重构。最近，长链非编码 RNA（LncRNA）被发现参与心肌肥厚的生理和病理过程。在这项研究中，我们发现 LncRNA KCND1（LncKCND1）在主动脉缩窄（TAC）诱导的肥厚小鼠心脏和血管紧张素 II（Ang II）诱导的新生小鼠心肌细胞中均下调。进一步分析表明，LncKCND1 的敲低会损害心肌线粒体功能，并导致心肌细胞发生肥厚变化。相比之下，LncKCND1 的过表达抑制了 Ang II 诱导的心肌细胞肥厚变化。重要的是，增强 LncKCND1 的表达可保护心脏免受 TAC 诱导的病理性心肌肥厚，并改善 TAC 小鼠的心脏功能。随后的质谱分析和 RNA 免疫沉淀实验表明，LncKCND1 可直接与 YBX1 结合。此外，LncKCND1 的过表达上调了 YBX1 的表达水平，而沉默 LncKCND1 则产生相反的效果。此外，YBX1 在心肌肥厚期间下调，而过表达 YBX1 可抑制 Ang II 诱导的心肌细胞肥厚。此外，沉默 YBX1 逆转了 LncKCND1 对心肌细胞线粒体功能的影响及其在心肌肥厚中的保护作用，表明 YBX1 是 LncKCND1 调节心肌肥厚的下游靶标。总之，我们的研究为 LncKCND1 的作用机制提供了深入的见解，并支持将 LncKCND1 作为病理性心肌肥厚的潜在治疗靶点。
