Selective YAP/TAZ inhibition in fibroblasts via dopamine receptor D1 agonism reverses fibrosis

Abstract

Tissue fibrosis is characterized by uncontrolled deposition and diminished clearance of fibrous connective tissue proteins, ultimately leading to organ scarring. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have recently emerged as pivotal drivers of mesenchymal cell activation in human fibrosis. Therapeutic strategies inhibiting YAP and TAZ have been hindered by the critical role that these proteins play in regeneration and homeostasis in different cell types. Here, we find that the Gαs-coupled dopamine receptor D1 (DRD1) is preferentially expressed in lung and liver mesenchymal cells relative to other resident cells of these organs. Agonism of DRD1 selectively inhibits YAP/TAZ function in mesenchymal cells and shifts their phenotype from profibrotic to fibrosis resolving, reversing in vitro extracellular matrix stiffening and in vivo tissue fibrosis in mouse models. Aromatic l-amino acid decarboxylase [DOPA decarboxylase (DDC)], the enzyme responsible for the final step in biosynthesis of dopamine, is decreased in the lungs of subjects with idiopathic pulmonary fibrosis, and its expression inversely correlates with disease severity, consistent with an endogenous protective role for dopamine signaling that is lost in pulmonary fibrosis. Together, these findings establish a pharmacologically tractable and cell-selective approach to targeting YAP/TAZ via DRD1 that reverses fibrosis in mice.

Macrophage-derived netrin-1 drives adrenergic nerve–associated lung fibrosis

“…The potential benefit of α 1 adrenergic antagonism will require replication in prospectively conducted, appropriately controlled studies including female patients. The effect of noradrenaline on ADRA1 receptor-expressing stromal and immune cells requires further investigation, and the role of other nerve-derived catecholamines such as dopamine should also be assessed (54). Unraveling the Collagen quantification.…”

In Vivo Metabolic Response upon Exposure to Gold Nanorod Core/Silver Shell Nanostructures: Modulation of Inflammation and Upregulation of Dopamine

“…Dopamine is an agonist of dopaminergic receptors. It is reported that dopamine receptor D1 agonism promoted reversal of experimental lungs and liver fibrosis [34]. After treatment with Au@Ag NRs, the elevated production of endogenous dopamine might be related with tissue injury and repair.…”

Mechanical Feed-Forward Loops Contribute to Idiopathic Pulmonary Fibrosis

“…80 Excitingly, pharmacologic inhibition of YAP/TAZ with Ga s -coupled dopamine receptor D1 reverses bleomycin-induced fibrosis in mice when administered starting 10 days after bleomycin injury. 81 Systemic YAP/TAZ inhibition with the receptor agonist ACT-333679 also illustrates the antifibrotic effects in vitro. 82 The myocardin-related transcription factors (MRTFs) A and B act as cofactors for serum response factor; they are mechanosensitive transcription factors that regulate genes encoding structural and regulatory effectors of actin dynamics.…”