MiRNA networks mediate a compensatory response in heart failure induced cognitive impairment [RNA-Seq]

Heart failure (HF) is associated with an increased risk of cognitive impairment and hippocampal dysfunction, yet the underlying molecular mechanisms remain poorly understood. In this study, we utilized CaMKIIdC transgenic (TG) mice, a model for HF, to investigate the role of microRNA (miRNA) networks in hippocampus-dependent memory recovery. While 3-month-old CaMKIIdC TG mice displayed significant memory deficits and dysregulated hippocampal gene expression, these impairments were no longer detectable at 6 months, despite persistent cardiac dysfunction. Small RNA sequencing revealed a dynamic shift in hippocampal miRNA expression between 3 and 6 months old CaMKIIdC TG mice , with 27 miRNAs, termed "compensatory miRs," targeting 73% of reinstated transcripts and mediating transcriptional homeostasis. Notably, miR-181a-5p emerged as a central hub in the compensatory miRNA network, with its downregulation aligning with restored neuronal function and memory. These findings highlight a synergistic miRNA response that compensates for early transcriptional deficits in HF. In conclusion, our results suggest that better understanding of these microRNA networks may provide novel therapeutic targets to manage heart failure related cognitive dysfunctions. Overall design: RNA-seq profiling from CaMKIIdC transgenic mice and wildtype controls at 6 months of age.

心力衰竭（HF）与认知障碍及海马功能障碍风险升高密切相关，但其潜在分子机制仍未得到充分阐明。本研究以心力衰竭模型——CaMKIIdC转基因（TG）小鼠为实验对象，探究微小RNA（miRNA）网络在海马依赖型记忆恢复中的作用。3月龄的CaMKIIdC TG小鼠表现出显著的记忆缺陷与海马基因表达失调，但尽管心脏功能障碍持续存在，上述损伤在6月龄时已无法检测到。小RNA测序结果显示，3月龄与6月龄CaMKIIdC TG小鼠的海马miRNA表达存在动态变化，其中27种被称为“补偿性miRs”的miRNA可靶向73%的恢复表达转录本，介导转录稳态。值得注意的是，miR-181a-5p作为补偿性miRNA网络的核心枢纽，其表达下调与神经元功能及记忆的恢复高度一致。本研究结果揭示了一种协同性miRNA应答机制，可补偿心力衰竭早期出现的转录缺陷。综上，本研究结果表明，深入解析此类miRNA网络可为心力衰竭相关认知功能障碍的治疗提供全新靶点。整体实验设计：对6月龄CaMKIIdC TG小鼠及野生型对照组进行RNA测序谱分析。