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Runt-related transcription factor 1 (Runx1) aggravates pathological cardiac hypertrophy by promoting p53 expression.

ABSTRACT: Cardiac hypertrophy and the resultant heart failure are among the most common causes of morbidity and mortality worldwide; thus, identifying the key factor mediating pathological cardiac hypertrophy is critically important for developing the strategy to protect against heart failure. Runx1 (Runt-related transcription factor 1) acts as an essential transcription factor that functions in a variety of cellular processes including differentiation, proliferation, tissue growth and DNA damage response. However, relatively little is known about the role of Runx1 in heart, especially cardiac hypertrophy and heart failure. In the present study, we investigated the role of Runx1 in experimentally pathological cardiac hypertrophy. The in vitro model was induced by Ang II exposure to cultured neonatal rat cardiomyocytes, and the in vivo pathological cardiac hypertrophy models were induced by chronic pressure overload in mice. Runx1 expression is increased in heart tissues from mice with pressure overload-induced cardiac hypertrophy and in neonatal rat cardiomyocytes in response to Ang II stimulation. Moreover, knockdown of cardiac Runx1 alleviates the pressure overload-induced cardiac hypertrophy. Mechanistically, Runx1 activates the p53 signalling by binding to the p53 gene and promotes its transcription. Rescue experiments indicate that Runx1 promotes cardiac hypertrophy in a p53-dependent manner. Remarkably, we demonstrated that Ro5-3335 (a Runx1 inhibitor) acts as a potential therapeutic drug for treating pathological cardiac hypertrophy. In summary, we conclude that Runx1 is a novel mediator and therapeutic target for pathological cardiac hypertrophy.

SUBMITTER: Zhang D

PROVIDER: S-EPMC8358850 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The somatic sensory neurons in dorsal root ganglia (DRG) detect and transmit a diverse array of sensory modalities, such as pain, itch, cold, warm, touch, and others. Recent genetic and single-cell RNA sequencing studies have revealed a group of DRG neurons that could be particularly relevant for acute and chronic itch information transmission. They express the natriuretic peptide type B (NPPB), as well as a cohort of receptors and neuropeptides that have been implicated in chronic itch manifestation, including the interleukin-31 receptor A (IL-31ra) and its coreceptor oncostatin M receptor (Osmr), the cysteinyl leukotriene receptor 2 (Cysltr2), somatostatin, and neurotensin. However, how these neurons are generated during development remains unclear. Here we report that Runx1 is required to establish all these molecular features of NPPB+ neurons. We further show that while early embryonic Runx1 activity is required for the formation of NPPB+ cells, at later stages Runx1 switches to a genetic repressor and thus its downregulation becomes a prerequisite for the proper development of these pruriceptors. This mode by Runx1 is analogous to that in controlling another group of pruriceptors that specifically express the chloroquine receptor MrgprA3. Finally, behavioral studies using both sexes of mice revealed marked deficits in processing acute and chronic itch in Runx1 conditional knock-out mice, possibly attributable to impaired development of various pruriceptors.SIGNIFICANCE STATEMENT Our studies reveal a generalized control mode by Runx1 for pruriceptor development and consolidate a hierarchical control mechanism for the formation of sensory neurons transmitting distinct modalities. Among dorsal root ganglion neurons that initially express the neurotrophin receptor TrkA, Runx1 is necessary for the proper development of those neurons that innervate tissues derived from the ectoderm such as skin epidermis and hair follicles. These Runx1-dependent cutaneous sensory neurons are then divided into two groups based on persistent or transient Runx1 expression. The Runx1-persistent group is involved in transmitting mechanical and thermal information, whereas the Runx1-transient group transmits pruriceptive information. Such hierarchical control mechanisms may provide a developmental solution for the formation of sensory circuits that transmit distinct modalities.

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Runt-related transcription factor 1 (Runx1) aggravates pathological cardiac hypertrophy by promoting p53 expression.

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