MiRNA networks mediate a compensatory response in heart failure induced cognitive impairment [smallRNA-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: Non coding RNA-seq profiling from CaMKIIdC transgenic mice and wildtype controls at 6 months and 3 months of age.