A tRNA-derived small RNA orchestrates cardioprotection through distinct cell-type-specific mechanisms
Pathological cardiac fibrosis and hypertrophy, key contributors to adverse remodeling that drives heart failure (HF), are not adequately targeted by current therapies. We identified tRNA-Asp-GTC-3'tDR, an ischemia-induced tRNA-derived small RNA (tDR), as an endogenous regulator of both remodeling processes across cardiac fibroblasts and cardiomyocytes. In murine models of myocardial ischemia- and…
Ischemia-induced tRNA-Asp-GTC-3 tDR emerges as an endogenous regulator that orchestrates cardioprotection through unique cell-type-specific mechanisms. In models of myocardial ischemia- and pressure overload-induced heart failure, the administration of tRNA-Asp-GTC-3 tDR to mice mitigated fibrosis and hypertrophy, safeguarded cardiac function, and enhanced survival, with just three doses offering long-lasting protection after ischemia.
Unexpectedly, tRNA-Asp-GTC-3 tDR exerts its protective effects via distinct pathways in different cell types. In cardiac fibroblasts, it forms stress granules that trap ribosome-loaded profibrotic transcripts, while in cardiomyocytes, it activates RNA autophagy by stimulating pseudouridine synthase PUS7. Its regulatory role and functional consequences were validated in human cardiac cells and tissues.
These findings reveal that a single tDR can coordinate cell-type-specific protective programs in the heart, indicating a promising new therapeutic avenue to curb heart failure progression.
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