Wednesday, April 2, 2025
4/2/2025
A novel strategy for heart failure therapeutics - Abstract Heart failure is a complex and heterogeneous clinical syndrome with significant morbidity and mortality worldwide. Regardless of the heart failure etiology, cardiomyocytes initially develop adaptive morphological hypertrophy that tends to reduce wall stress and prevent cardiac dysfunction, followed by transition to maladaptive decompensation that ultimately leads to heart failure. Understanding the transcriptome reconfiguration during transition can aid in preventing pathologic hypertrophy, the key driver of heart failure. Recent advances in next-generation sequencing have dramatically expanded the scope of cardiac transcriptome to non-coding RNAs, including microRNAs (miRNAs). Our preliminary studies discovered a novel miRNA (miR- 128) that is aberrantly upregulated in mouse and human failing hearts. The contributory role of miR-128 toward heart failure was documented in a pilot study showing that cardiomyocyte-specific miR-128 overexpression in mice causes eccentric cardiomyocyte hypertrophy with deteriorating cardiac functions. Mechanistically, we found that the increased miR-128 in failing cardiomyocytes is due to epigenetic changes with hypomethylation of the enhancer sequence in miR-128, leading to elevated recruitment of upstream transcription factor-1 (USF1) to enhance miR-128 transcription. Additional mechanistic studies with affinity RNA pull-down followed by mass spectrometry analysis revealed miR-128 interaction with the nucleocytoplasmic shuttling protein HNRNPA1. Moreover, this protein is translocated into the mitochondria during cardiomyocyte failure, thereby also increasing import of miR-128 into the mitochondria. In the mitochondria, miR-128 interacts with the heavy-strand promoter (HSP) of mitochondria DNA (mtDNA) to suppress mitochondria DNA transcription thus leading to mitochondria dysfunction and cardiomyocyte death. Based on these initial findings, we hypothesize that miR-128 inhibition can reduce or prevent cardiac pathological hypertrophy in response to stress by directly reversing or ameliorating mitochondria abnormality associated with cardiomyocyte failure. Specifically, we propose that applications of epigenetic editing system containing sgRNA (targeting to USF1 motif in miR-128 enhancer) and scFv-GCN4- DNMT3a (methylation of miR-128 enhancer) to silence miR-128 before or during early stages of cardiac remodeling are effective strategies to alleviate stress-induced cardiac damage and reduce the mortality and morbidity of heart failure. Three Specific Aims are proposed to test this hypothesis: Aim 1 will identify the mechanism by which miR-128 contributes to cardiac pathological hypertrophy in mouse and human cellular models, and evaluate the effects of miR-128 on pathological hypertrophy during cardiac remodeling. Aim 2 will elucidate the mechanism underlying the impaired mitochondria homeostasis induced by miR-128 and the trafficking mechanism of miRNA into the mitochondria. Aim 3 will interrogate the epigenetic mechanism of aberrant miR-128 expression in heart failure, and test the hypothesis that epigenetic silencing of miR-128 enhancer is a viable therapeutic approach to prevent pathological hypertrophy during cardiac remodeling.
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