Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling

Abstract

Propionic acid is a cell nutrient but also a stimulus for cellular signaling. Free fatty acid receptor (FFAR)-3, also known as GPR41, is a Gi/o protein-coupled receptor (GPCR) that mediates some of the propionate’s actions in cells, such as inflammation, fibrosis, and increased firing/norepinephrine release from peripheral sympathetic neurons. The regulator of G-protein Signaling (RGS)-4 inactivates (terminates) both Gi/o- and Gq-protein signaling and, in the heart, protects against atrial fibrillation via calcium signaling attenuation. RGS4 activity is stimulated by β-adrenergic receptors (ARs) via protein kinase A (PKA)-dependent phosphorylation. Herein, we examined whether RGS4 modulates cardiac FFAR3 signaling/function. We report that RGS4 is essential for dampening of FFAR3 signaling in H9c2 cardiomyocytes, since siRNA-mediated RGS4 depletion significantly enhanced propionate-dependent cAMP lowering, Gi/o activation, p38 MAPK activation, pro-inflammatory interleukin (IL)-1β and IL-6 production, and pro-fibrotic transforming growth factor (TGF)-β synthesis. Additionally, catecholamine pretreatment blocked propionic acid/FFAR3 signaling via PKA-dependent activation of RGS4 in H9c2 cardiomyocytes. Finally, RGS4 opposes FFAR3-dependent norepinephrine release from sympathetic-like neurons (differentiated Neuro-2a cells) co-cultured with H9c2 cardiomyocytes, thereby preserving the functional βAR number of the cardiomyocytes. In conclusion, RGS4 appears essential for propionate/FFAR3 signaling attenuation in both cardiomyocytes and sympathetic neurons, leading to cardioprotection against inflammation/adverse remodeling and to sympatholysis, respectively.

Immunosuppressants Tacrolimus and Sirolimus revert the cardiac antifibrotic properties of p38-MAPK inhibition in 3D-multicellular human iPSC-heart organoids

“…Of particular interest, we found up-regulated transcripts of Vdac1/2 related to Calcium signaling and Mapk11, 13, and 14, encoding for different isoforms of the MAP-kinase p38 (β, γ and α isoforms, respectively), indicating that both Calcium signaling and p38-MAPK have important roles in the establishment of the fibrosis Frontiers in Cell and Developmental Biology frontiersin.org pathway. RGS proteins have been proposed to have implications in establishing the fibrosis transcriptional program in cardiac fibroblasts upstream p38-MAPK pathway, mainly via the Rgs4 expression (Miao et al, 2016;Carbone et al, 2022). We analyzed RGS gene expression levels and found that most of them are poorly represented in healthy CFs (Supplementary Figure S2A).…”

Autonomic Nervous System Regulation of Epicardial Adipose Tissue: Potential Roles for Regulator of G Protein Signaling-4

“…Finally, we recently reported on the crucial role of RGS4 in regulation of the free fatty acid receptor (FFAR)3, also known as GPR41 [ 89 ]. FFAR3 is a GPCR activated by short chain fatty acids, e.g., propionate, butyrate, and regulates cardiovascular function via effects in peripheral sympathetic neurons, wherein it promotes neuronal firing and NE synthesis/release [ 90 ].…”

“…FFAR3 is a GPCR activated by short chain fatty acids, e.g., propionate, butyrate, and regulates cardiovascular function via effects in peripheral sympathetic neurons, wherein it promotes neuronal firing and NE synthesis/release [ 90 ]. RGS4 was found to inactivate cardiac FFAR3 G i/o protein signaling, resulting in cardioprotection against short chain fatty acid-dependent pro-inflammatory and pro-fibrotic effects [ 89 ]. In addition, cardiac βARs stimulate RGS4 to impede this FFAR3 signaling [ 89 ].…”

“…RGS4 was found to inactivate cardiac FFAR3 G i/o protein signaling, resulting in cardioprotection against short chain fatty acid-dependent pro-inflammatory and pro-fibrotic effects [ 89 ]. In addition, cardiac βARs stimulate RGS4 to impede this FFAR3 signaling [ 89 ]. Importantly, RGS4 also opposed FFAR3-dependent NE release from sympathetic neurons co-cultured with cardiac myocytes, thereby preserving cardiac βAR function [ 89 ].…”

“…In addition, cardiac βARs stimulate RGS4 to impede this FFAR3 signaling [ 89 ]. Importantly, RGS4 also opposed FFAR3-dependent NE release from sympathetic neurons co-cultured with cardiac myocytes, thereby preserving cardiac βAR function [ 89 ]. This provides another line of evidence for the cardioprotective role of RGS4 against inflammation and fibrosis, two maladaptive processes of the heart known to lead to AFib, arrhythmias, and heart failure [ 91 , 92 ].…”