Nuclear AGO2 exacerbated high-fat diet-induced heart failure by activating transcription of HMGCS2 to promote ketogenesis in the heart

Background and Aims With the changes in life-style, the incidence of hyperlipidemia-related heart failure (HF) is gradually increasing. Recent studies suggested that microRNAs (miRNAs) located in different subcellular organelles could regulate lipid metabolism and cardiac function. However, the functional property of subcellular AGO2, the core member of miRNA machinery, remained elusive in hyperlipidemia-related HF. Methods We revealed the causal role of nuclear AGO2 in inducing cardiac dysfunction with a recombinant adeno-associated virus (serotype 9) vector. The underlying mechanisms were explored with echocardiography, catheter manometer system, proteomics analyses, chromatin immunoprecipitation assays, luciferase assays, Western blotting, immunofluorescence, seahorse assays, β-hydroxybutyrate and ATP measurements. Results We explored that knockdown of AGO2 attenuated high-fat diet (HFD)-induced cardiac dysfunction. Mechanistically, AGO2 could activate the transcription of HMGCS2. Knockdown of either cardiac AGO2 or HMGCS2 protected against cardiac dysfunction in HFD-induced HF. Subsequent high-through profiling further identified ATP5F1E and UQCR10 as the key downstream targets for AGO2/HMGCS2 mediated β-hydroxybutyrate over-production, and we revealed a feed forward loop involving lipo-toxicity and ketone-toxicity. Furthermore, we demonstrated a PKCα-ERK-EGR1-AGO2-HMGCS2 axis in the initiation of fatty acids-induced cardiomyocyte dysfunction. Importantly, we found that overexpressing of nuclear AGO2 rather than cytosolic AGO2 exacerbated the cardiac dysfunction in HFD-induced HF mice. Conclusions Our findings uncover that AGO2/HMGCS2 pathway links lipo-toxicity to ketone-toxicity in the heart, which provides new mechanistic insights and suggests a potential strategy to develop treatments against hyperlipidemia-associated cardiovascular complications.