tRNA-derived Small RNAs and their Potential Roles in the Therapeutic Heterogeneity of Sacubitril/valsartan in Heart Failure Patients after Acute Myocardial Infarction

Background: It has been reported that sacubitril/valsartan can improve cardiac function in acute myocardial infarction (AMI) patients complicated by heart failure (HF). However, a number of patients cannot be treated successfully; this phenomenon is called sacubitril/valsartan resistance (SVR), and the mechanisms remain unclear. Methods:In our present research, the expression profiles of tRNA-derived small RNAs (tsRNAs) in SVR along with NSVR patients were determined by RNA sequencing. Through bioinformatics, qRT–PCR, and cell-based experiments, we identified SVR-related tsRNAs and confirmed their diagnostic value, predicted their targeted genes, and explored the enriched signal pathways as well as regulatory roles of tsRNAs in SVR. Results:Our research indicated that 36 tsRNAs were upregulated and that 21 tsRNAs were downregulated in SVR. Among these tsRNAs, the expression of tRF-59:76-Tyr-GTA-2-M3 and tRF-60:76-Val-AAC-1-M5 was upregulated, while the expression of tRF-1:29-Gly-GCC-1 was downregulated in the group of SVR. Receiver operating characteristic (ROC) curve analysis demonstrated that these three tsRNAs were potential biomarkers of the therapeutic heterogeneity of sacubitril/valsartan. Moreover, tRF-60:76-Val-AAC-1-M5 might target Tnfrsf10b and Bcl2l1 to influence the observed therapeutic heterogeneity through the lipid and atherosclerosis signaling pathways. Conclusions:Hence, tsRNA might play a vital role in SVR. These discoveries provide new insights for the mechanistic investigation of responsiveness to sacubitril/valsartan. Overall design: the expression profiles of tRNA-derived small RNAs (tsRNAs) in SVR along with NSVR patients were determined by RNA sequencing. Through bioinformatics, qRT–PCR, and cell-based experiments, we identified SVR-related tsRNAs and confirmed their diagnostic value, predicted their targeted genes, and explored the enriched signal pathways as well as regulatory roles of tsRNAs in SVR.

背景：已有研究表明，沙库巴曲缬沙坦（sacubitril/valsartan）可改善急性心肌梗死（acute myocardial infarction, AMI）合并心力衰竭（heart failure, HF）患者的心功能。然而仍有部分患者无法获得理想的治疗效果，该现象被称为沙库巴曲缬沙坦耐药（sacubitril/valsartan resistance, SVR），其具体作用机制尚未阐明。
方法：本研究通过RNA测序技术，检测了沙库巴曲缬沙坦耐药（SVR）患者与非耐药（non-SVR, NSVR）患者体内tRNA衍生小RNA（tRNA-derived small RNAs, tsRNAs）的表达谱。通过生物信息学分析、qRT–PCR及细胞实验，我们筛选出与SVR相关的tsRNAs，验证了其诊断价值，预测了其靶基因，并探究了tsRNAs在SVR发生过程中富集的信号通路及其调控作用。
结果：本研究发现，SVR患者体内共有36种tsRNAs表达上调、21种tsRNAs表达下调。其中，tRF-59:76-Tyr-GTA-2-M3与tRF-60:76-Val-AAC-1-M5的表达水平显著升高，而tRF-1:29-Gly-GCC-1的表达水平则显著降低。受试者工作特征（Receiver operating characteristic, ROC）曲线分析显示，上述3种tsRNAs可作为沙库巴曲缬沙坦治疗异质性的潜在生物标志物。此外，tRF-60:76-Val-AAC-1-M5可能通过靶向Tnfrsf10b与Bcl2l1基因，经脂质代谢与动脉粥样硬化信号通路影响沙库巴曲缬沙坦的治疗异质性。
结论：综上，tsRNAs可能在SVR的发生发展中发挥关键作用。本研究成果为沙库巴曲缬沙坦治疗响应性的机制研究提供了全新视角。
总体设计：本研究通过RNA测序技术，检测了SVR患者与NSVR患者体内tRNA衍生小RNA（tsRNAs）的表达谱。通过生物信息学分析、qRT–PCR及细胞实验，筛选出与SVR相关的tsRNAs，验证其诊断价值，预测靶基因，并探究了tsRNAs在SVR中富集的信号通路及其调控作用。