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Nuclear AGO2 promotes myocardial remodeling by activating ANKRD1 transcription in failing hearts.
Molecular Therapy 2024 March 12
Heart failure (HF) is manifested by transcriptional and post-transcriptional reprogramming of critical genes. Multiple studies have revealed that microRNAs could translocate into subcellular organelles such as nucleus to modify gene expression. However, the functional property of subcellular Argonaute2 (AGO2), the core member of the microRNA machinery, has remained elusive in HF. AGO2 was found to be localized in both cytoplasm and nucleus of cardiomyocytes, and robustly increased in failing hearts of patients and animal models. We demonstrated nuclear AGO2 rather than cytosolic AGO2 overexpression by recombinant adeno-associated virus (serotype 9) with cardiomyocyte-specific troponin T promoter exacerbated the cardiac dysfunction in transverse aortic constriction (TAC)-operated mice. Mechanistically, nuclear AGO2 activates the transcription of ANKRD1, encoding Ankyrin repeat domain-containing protein 1 (ANKRD1), which also has a dual function in the cytoplasm as part of I-band of the sarcomere and in the nucleus as a transcriptional cofactor. Overexpression of nuclear ANKRD1 recaptured some key features of cardiac remodeling by inducing pathological MYH7 activation, whereas cytosolic ANKRD1 seemed cardio-protective. For clinical practice, we found ivermectin, an anti-parasite drug, and ANPep, a ANKRD1 nuclear location signal mimetic peptide, were able to prevent ANKRD1 nuclear import, resulting in the improvement of cardiac performance in TAC-induced HF.
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