Key result
Erk3 deficiency or estrone sulfate limits pressure-induced cardiac remodeling and dysfunction in mice.
Why the study?
The role and downstream signaling mechanisms of myocardial ERK3 in pressure overload-induced pathological cardiac remodeling remain unclear.
Does cardiomyocyte-specific Erk3 deficiency or estrone sulfate treatment prevent pathological cardiac remodeling and dysfunction in models of pressure overload?
Does cardiomyocyte-specific Erk3 deficiency or estrone sulfate treatment prevent pathological cardiac remodeling and dysfunction in models of pressure overload?
Estrone sulfate acts as a novel inhibitor of the ALY-ERK3 signaling pathway, offering a potential therapeutic strategy to attenuate pressure overload-induced pathological cardiac remodeling.
Estrone sulfate may inhibit ALY-ERK3 signaling to attenuate hypertrophy; hypothesis-generating in animal models and leaves open human translation.
Pathological cardiac remodeling is a significant contributor to heart failure and mortality. Studies have demonstrated that extracellular signal regulated kinase 3 (ERK3) in cardiac fibroblasts aggravates pressure overload-evoked pathological cardiac remodeling via mitogen activated protein kinase-activated protein kinase-5 (MK5). However, myocardial ERK3 does not activate MK5, thus the role of myocardial ERK3 remains unclear. Through in vivo and in vitro experiments, we revealed that myocardial ERK3 expression increases under pressure overload and the protein accumulates significantly in the nucleus. Using cardiomyocyte-specific Erk3 -deficient mice, neonatal rat cardiomyocytes and adult mouse cardiomyocytes, we found that cardiomyocyte-specific Erk3 deficiency ameliorated pressure overload-induced pathological cardiac remodeling in vivo. Co-immunoprecipitation, mass spectrometry, and single nucleus RNA sequencing were used to analyse for the nuclear translocation and downstream signaling mechanisms of ERK3. Specifically, pressure overload enhances the binding of Aly/REF export factor (ALY) to ERK3, resulting in the truncation of the ERK3 C-terminal and its subsequent nuclear translocation to activate the thioredoxin-interacting protein (TXNIP)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) pathway through the expression of the splicing factor proline and glutamine rich (SFPQ). To screen for targeted drugs, we conducted a virtual screening and identified estrone sulfate as an inhibitor of ALY to counteract hypertrophic effects. Collectively, our findings indicate that estrone sulfate functions as a novel inhibitor of the ALY-ERK3 signaling pathway, potentially serving as a promising therapeutic candidate for the management of pathological cardiac remodeling.
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Zhou et al. (2026) studied Pathological cardiac remodeling. Cardiomyocyte-specific Erk3 knockout and Estrone sulfate vs. Control / Vehicle was evaluated on Cardiac function (ejection fraction, fractional shortening) and hypertrophic markers. Cardiomyocyte-specific Erk3 deficiency or treatment with estrone sulfate ameliorated pressure overload-induced pathological cardiac remodeling and dysfunction in mice.
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