Saturday, May 31, 2025
5/31/2025
Integrative role of Rps6kb1 in pathological cardiac remodeling - Project Summary Heart failure is a leading cause of morbidity and mortality worldwide. Hypertension is one of the most important risk factors of heart failure. Despite paramount interests and urgent clinical needs, our understanding of the mechanisms of heart failure development remains limited. To accommodate the elevated demand of cardiac contractility under high blood pressure, the heart mounts an acute reaction through cardiomyocyte hypertrophic growth. This once adaptive response may decompensate and progress into heart failure. The long- term goal of this project is to identify novel mechanisms of the pathological transition from adaptive cardiac hypertrophy to heart failure and explore therapeutic interventions. With an unbiased phosphoproteomic analysis, Rps6kb1 was identified as one of the most prominent kinases in cardiomyocyte hypertrophic growth. Rps6kb1 is a classical downstream target of mTOR, however, its role in hypertensive heart disease remains incompletely understood. Moreover, Rps6kb1, with its complex activation mechanism, may integrate signals from multiple upstream pathways, above and beyond the mTOR signaling. Preliminary studies showed that Rps6kb1 deletion in the heart suppresses adaptive cardiac hypertrophic growth and consequently, cardiomyopathy and heart failure are accelerated under pressure overload. Based on these findings, a central hypothesis is formulated that Rps6kb1 is an essential player in adaptive hypertrophic growth by integrating signals from multiple upstream pathways. Additional preliminary data showed that Rps6kb1 is directly phosphorylated by ERK, independent of the mTOR signaling. A novel threonine site of phosphorylation by ERK was later identified by mass spectrometry. More importantly, ERK-mediated phosphorylation of Rps6kb1 is required for full Rps6kb1 activation. Further pilot tests demonstrated that Rps6kb1 is subjected to another post-translational modification, K63 polyubiquitination. Lysine 85 was identified as the critical site for this modification through multiple mutagenesis assays, and Lys85Ala mutation strongly diminished both ubiquitination and activation of Rps6kb1. In this grant application, the role of ERK-mediated phosphorylation of Rps6kb1 will be further characterized, and its implications in adaptive hypertrophic growth and heart failure will be illustrated using both gain- and loss-of-function mouse models. In addition, the relevance and significance of Lys85 ubiquitination in hypertensive heart disease will be delineated by identification of the responsible E3 ligase and evaluation of the novel Lys85Ala knock-in mouse model. Moreover, the interplay between this novel phosphorylation and this new ubiquitination in cardiac hypertrophy will be interrogated. Primary cardiomyocyte culture will be employed to complement in vivo animal models at the mechanistic level. Elucidation of the role of Rps6kb1 as an integrative player in pathological cardiac remodeling will advance our understanding of hypertensive heart disease and heart failure and pave a way for novel, more effective therapeutic design.
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