Key result
Cardiac ric-8b deletion in mice severely impairs contractility and drives fibrosis, likely via Gαs.
Why the study?
Ric-8 proteins modulate G-protein function, but little is known of their potential physiological importance in the heart.
The ric-8b protein is essential to preserve cardiac contractile function, likely through interaction with the stimulatory G-protein Gαs and downstream phosphorylation of myosin light chain 2.
Answers are grounded in this paper and cite their sources.
Ric-8b supports murine cardiac contractility; leaves open its role and therapeutic potential in human heart failure.
Resistance to inhibitors of cholinesterases (ric-8 proteins) are involved in modulating G-protein function, but little is known of their potential physiological importance in the heart. In the present study, we assessed the role of resistance to inhibitors of cholinesterase 8b (Ric-8b) in determining cardiac contractile function. We developed a murine model in which it was possible to conditionally delete ric-8b in cardiac tissue in the adult animal after the addition of tamoxifen. Deletion of ric-8b led to severely reduced contractility as measured using echocardiography days after administration of tamoxifen. Histological analysis of the ventricular tissue showed highly variable myocyte size, prominent fibrosis, and an increase in cellular apoptosis. RNA sequencing revealed transcriptional remodeling in response to cardiac ric-8b deletion involving the extracellular matrix and inflammation. Phosphoproteomic analysis revealed substantial downregulation of phosphopeptides related to myosin light chain 2. At the cellular level, the deletion of ric-8b led to loss of activation of the L-type calcium channel through the β-adrenergic pathways. Using fluorescence resonance energy transfer-based assays, we showed ric-8b protein selectively interacts with the stimulatory G-protein, Gαs. We explored if deletion of Gnas (the gene encoding Gαs) in cardiac tissue using a similar approach in the mouse led to an equivalent phenotype. The conditional deletion of the Gαs gene in the ventricle led to comparable effects on contractile function and cardiac histology. We conclude that ric-8b is essential to preserve cardiac contractile function likely through an interaction with the stimulatory G-protein and downstream phosphorylation of myosin light chain 2.
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Tsisanova et al. (2024) studied Cardiac contractile function. Conditional deletion of ric-8b was evaluated on Cardiac contractile function. Conditional deletion of ric-8b in adult murine cardiac tissue led to severely reduced contractility, prominent fibrosis, and increased apoptosis, likely through interaction with Gαs.
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