scholarly journals B-arrestin-2 Signaling Is Important to Preserve Cardiac Function During Aging

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrielle E. Capote ◽  
Ashley Batra ◽  
Chad M. Warren ◽  
Shamim A. K. Chowdhury ◽  
Beata M. Wolska ◽  
...  
Keyword(s):  
Cardiac Function ◽  
G Protein ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
G Protein Signaling ◽  
Ang Ii ◽  
Protein Signaling ◽  
Signaling Mechanism ◽  
Knock Out ◽  
Adaptive Signal

Experiments reported here tested the hypothesis that β-arrestin-2 is an important element in the preservation of cardiac function during aging. We tested this hypothesis by aging β-arrestin-2 knock-out (KO) mice, and wild-type equivalent (WT) to 12–16months. We developed the rationale for these experiments on the basis that angiotensin II (ang II) signaling at ang II receptor type 1 (AT1R), which is a G-protein coupled receptor (GPCR) promotes both G-protein signaling as well as β-arrestin-2 signaling. β-arrestin-2 participates in GPCR desensitization, internalization, but also acts as a scaffold for adaptive signal transduction that may occur independently or in parallel to G-protein signaling. We have previously reported that biased ligands acting at the AT1R promote β-arrestin-2 signaling increasing cardiac contractility and reducing maladaptations in a mouse model of dilated cardiomyopathy. Although there is evidence that ang II induces maladaptive senescence in the cardiovascular system, a role for β-arrestin-2 signaling has not been studied in aging. By echocardiography, we found that compared to controls aged KO mice exhibited enlarged left atria and left ventricular diameters as well as depressed contractility parameters with preserved ejection fraction. Aged KO also exhibited depressed relaxation parameters when compared to WT controls at the same age. Moreover, cardiac dysfunction in aged KO mice was correlated with alterations in the phosphorylation of myofilament proteins, such as cardiac myosin binding protein-C, and myosin regulatory light chain. Our evidence provides novel insights into a role for β-arrestin-2 as an important signaling mechanism that preserves cardiac function during aging.

scholarly journals Fusarium verticillioides induces maize-derived ethylene to promote virulence by engaging fungal G-protein signaling

2021 ◽  
Author(s):  
Yong-Soon Park ◽  
Eli J Borrego ◽  
Xiquan Gao ◽  
Shawn A Christensen ◽  
Eric Schmelz ◽  
...  
Keyword(s):  
G Protein ◽  
Fusarium Verticillioides ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Fusarium Ear Rot ◽  
Ear Rot ◽  
Knock Out ◽  
Seed Colonization ◽  
Meta Analyses ◽  
Exogenous Treatment

Seed maceration and contamination with mycotoxin fumonisin inflicted by Fusarium verticillioides is major disease of concern for maize producers world-wide. Meta-analyses of QTL for Fusarium ear rot resistance uncovered several ethylene (ET) biosynthesis and signaling genes within them, implicating ET in maize interactions with F. verticillioides. We tested this hypothesis using maize knock-out mutants of the 1-aminocyclopropane-1-carboxylate (ACC) synthases, ZmACS2 and ZmACS6. Infected wild-type seed emitted five-fold higher ET levels compared to controls, whereas ET was abolished in the acs2 and acs6 single and double mutants. The mutants supported reduced fungal biomass, conidia and fumonisin content. Normal susceptibility was restored in the acs6 mutant with exogenous treatment of ET precursor, ACC. Subsequently, we showed that fungal G-protein signaling is required for virulence via induction of maize-produced ET. F. verticillioides Gβ subunit and two regulators of G-protein signaling mutants displayed reduced seed colonization and decreased ET levels. These defects were rescued by exogenous application of ACC. We concluded that pathogen-induced ET facilitates F. verticillioides colonization of seed, and in turn host ET production is manipulated via G-protein signaling of F. verticillioides to facilitate pathogenesis.

scholarly journals Regulator of G protein signaling 2 is a functionally important negative regulator of angiotensin II-induced cardiac fibroblast responses

2011 ◽  
Vol 301 (1) ◽  
pp. H147-H156 ◽  
Author(s):  
Peng Zhang ◽  
Jialin Su ◽  
Michelle E. King ◽  
Angel E. Maldonado ◽  
Cindy Park ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Angiotensin Ii ◽  
G Protein ◽  
Cardiac Fibroblasts ◽  
Negative Regulator ◽  
G Protein Signaling ◽  
Ang Ii ◽  
Protein Signaling ◽  
Important Negative Regulator

Cardiac fibroblasts play a key role in fibrosis development in response to stress and injury. Angiotensin II (ANG II) is a major profibrotic activator whose downstream effects (such as phospholipase Cβ activation, cell proliferation, and extracellular matrix secretion) are mainly mediated via Gq-coupled AT1 receptors. Regulators of G protein signaling (RGS), which accelerate termination of G protein signaling, are expressed in the myocardium. Among them, RGS2 has emerged as an important player in modulating Gq-mediated hypertrophic remodeling in cardiac myocytes. To date, no information is available on RGS in cardiac fibroblasts. We tested the hypothesis that RGS2 is an important regulator of ANG II-induced signaling and function in ventricular fibroblasts. Using an in vitro model of fibroblast activation, we have demonstrated expression of several RGS isoforms, among which only RGS2 was transiently upregulated after short-term ANG II stimulation. Similar results were obtained in fibroblasts isolated from rat hearts after in vivo ANG II infusion via minipumps for 1 day. In contrast, prolonged ANG II stimulation (3–14 days) markedly downregulated RGS2 in vivo. To delineate the functional effects of RGS expression changes, we used gain- and loss-of-function approaches. Adenovirally infected RGS2 had a negative regulatory effect on ANG II-induced phospholipase Cβ activity, cell proliferation, and total collagen production, whereas RNA interference of endogenous RGS2 had opposite effects, despite the presence of several other RGS. Together, these data suggest that RGS2 is a functionally important negative regulator of ANG II-induced cardiac fibroblast responses that may play a role in ANG II-induced fibrosis development.

scholarly journals Increased Expression of Regulator of G Protein Signaling-2 (RGS-2) in Bartter’s/Gitelman’s Syndrome. A Role in the Control of Vascular Tone and Implication for Hypertension

2004 ◽  
Vol 89 (8) ◽  
pp. 4153-4157 ◽  
Author(s):  
Lorenzo A. Calò ◽  
Elisa Pagnin ◽  
Paul A. Davis ◽  
Michelangelo Sartori ◽  
Giulio Ceolotto ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
G Protein ◽  
Vascular Tone ◽  
Mononuclear Cells ◽  
G Protein Signaling ◽  
Ang Ii ◽  
Protein Signaling ◽  
Genetic Abnormalities ◽  
Dependent Protein ◽  
Vascular Hyporeactivity

Regulator of G protein signaling-2 (RGS-2) plays a key role in the G protein-coupled receptor (GPCR) angiotensin II (Ang II) signaling. NO and cGMP exert a vasodilating action also through activation and binding to RGS-2 of cGMP dependent protein kinase 1-α, which phosphorylates RGS-2 and dephosphorylates myosin light chain. In Bartter’s/Gitelman’s patients (BS/GS) Ang II related signaling and vasomotor tone are blunted. Experiments were planned to explore whether RGS-2 may play a role in BS/GS vascular hyporeactivity. NO metabolites and cGMP urinary excretion were also measured. Mononuclear cells (PBM) from six BS/GS patients and six healthy controls were used. PBM RGS-2 mRNA and RGS-2 protein were increased in BS/GS: 0.47 ± 0.06 d.u. vs 0.32 ± 0.04, (p < 0.006) (RGS-2 mRNA), and 0.692 ± 0.02 vs 0.363 ± 0.06 (p < 0.0001) (RGS2 protein). Incubation of PBM with Ang II increased RGS-2 protein in controls (from 0.363 ± 0.06 d.u. to 0.602 ± 0.05; p < 0.0001) but not in BS/GS (from 0.692 ± 0.02 to 0.711 ± 0.02). NO2-/NO3- and cGMP urinary excretion were increased in BS/GS (0.46 ± 0.13 vs 0.26 ± 0.05 μmol/μmol of urinary creatinine, p < 0.005, and 0.060 ± 0.030 vs 0.020 ± 0.01 p < 0.009, respectively). These results demonstrate that RGS-2 is increased and maximally stimulated in BS/GS and human RGS-2 system reacts as predicted by knockout mice experiments. This is the first report of RGS-2 level in a human clinical condition characterized by altered vascular tone, underlines the importance of RGS-2 as a key regulator element for Ang II signaling and provides insight into the links between BS/GS genetic abnormalities and abnormal vascular tone regulation.

scholarly journals Regulators of G-protein signaling 4 in adrenal gland: localization, regulation, and role in aldosterone secretion

2007 ◽  
Vol 194 (2) ◽  
pp. 429-440 ◽  
Author(s):  
Damian G Romero ◽  
Ming Yi Zhou ◽  
Licy L Yanes ◽  
Maria W Plonczynski ◽  
Tanganika R Washington ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
G Protein ◽  
Intracellular Signaling ◽  
Zona Glomerulosa ◽  
G Protein Signaling ◽  
Ang Ii ◽  
Protein Signaling ◽  
Aldosterone Secretion ◽  
H295r Cells

Regulators of G-protein signaling (RGS proteins) interact with Gα subunits of heterotrimeric G-proteins, accelerating the rate of GTP hydrolysis and finalizing the intracellular signaling triggered by the G-protein-coupled receptor (GPCR)–ligand interaction. Angiotensin II (Ang II) interacts with its GPCR in adrenal zona glomerulosa cells and triggers a cascade of intracellular signals that regulates steroidogenesis and proliferation. On screening for adrenal zona glomerulosa-specific genes, we found that RGS4 was exclusively localized in the zona glomerulosa of the rat adrenal cortex. We studied RGS4 expression and regulation in the rat adrenal gland, including the signaling pathways involved, as well as the role of RGS4 in steroidogenesis in human adrenocortical H295R cells. We reported that RGS4 mRNA expression in the rat adrenal gland was restricted to the adrenal zonal glomerulosa and upregulated by low-salt diet and Ang II infusion in rat adrenal glands in vivo. In H295R cells, Ang II caused a rapid and transient increase in RGS4 mRNA levels mediated by the calcium/calmodulin/calmodulin-dependent protein kinase and protein kinase C pathways. RGS4 overexpression by retroviral infection in H295R cells decreased Ang II-stimulated aldosterone secretion. In reporter assays, RGS4 decreased Ang II-mediated aldosterone synthase upregulation. In summary, RGS4 is an adrenal gland zona glomerulosa-specific gene that is upregulated by aldosterone secretagogues, in vivo and in vitro, and functions as a negative feedback of Ang II-triggered intracellular signaling. Alterations in RGS4 expression levels or functions may be involved in deregulations of Ang II signaling and abnormal aldosterone secretion.

Abstract P137: Knock Out Of Regulatory G Protein Signaling 2 Specifically In CD4 T Cells Prevents Angiotensin II Induced Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Sabrina M Scroggins ◽  
Gabrielle Gray ◽  
Monica C Myers ◽  
Sarah N Miller ◽  
Pablo Nakagawa ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
G Protein ◽  
Inflammatory Cytokines ◽  
Cd4 T Cells ◽  
G Protein Signaling ◽  
Ang Ii ◽  
Protein Signaling ◽  
Induced Hypertension ◽  
Anti Inflammatory

Preeclampsia (PreE) is a hypertensive disorder in pregnancy. Aberrations of Regulator of G protein Signaling (RGS) family members are associated with PreE and hypertension (HTN). We previously observed a 9-fold increase in RGS2 in CD4+ T cells during PreE. In total, our work suggests that modulating T cells may be a therapeutic strategy for HTN. We hypothesize that reducing RGS2 specifically in CD4+ T cells will restore anti-inflammatory T cell responses and prevent HTN. Utilizing an angiotensin (ANG) II infusion mouse model, we aimed to investigate 1) the impact of the loss of RGS2 in CD4+ T cells on cytokine production and 2) if the loss of RGS2 in CD4+ T cells will protect against the development of HTN. RGS2 was knocked-out in CD4+ T cells (CD4-Cre x RGS2 flox mice; KO ). CD4 RGS2 KO (n=5) or littermate control mice (CTL, n=3) were administered 490 ng/kg/min ANG II for 21 days via mini-osmotic pump. Blood pressure was assessed by radiotelemetry. ELISAs were performed to determine pro- and anti- inflammatory cytokine levels in tissues from KO (n=9) and CTL (n=8) mice. Pro-inflammatory cytokines IFNγ and IL-17 were not significantly different in the heart, kidney, liver or spleen of KO vs CTL mice. The anti-inflammatory cytokines IL-4 (KO 410 vs CTL 339 pg/mL, p<0.05) and TGFβ (KO 5.7x10 5 vs 5.0x10 5 pg/mL, p<0.05) were increased in the kidneys of KO mice compared to CTL mice. At baseline, KO and CTL mice showed no differences in 24-hr heart rate (HR), systolic or diastolic blood pressure (SBP and DBP, respectively). Throughout the study, KO mice had a significantly lower 24-hr SBP (Day 7: KO 132.3 vs CTL 149.7 mmHg, p<0.05; Day 14: KO 123.6 vs CTL 162.3 mmHg, p<0.05; Day 21: KO 118.3 vs 154.8 mmHg, p<0.05) and DBP (Day 7: KO 101.2 vs CTL 113.8 mmHg, p<0.05; Day 14: KO 98.4 vs CTL 121.8 mmHg, p<0.05; Day 21: KO 96.8 vs 116.4 mmHg, p<0.05) compared to CTL mice. The 24-hr HR was only significantly lower at three weeks ANG II (KO 493.4 vs CTL 540.6 bpm, p<0.05) compared to CTL mice. The increased levels of IL-4 and TGFβ observed in KO mice support a role of RGS2 in anti-inflammatory immune responses. In accordance with our hypothesis, the loss of RGS2, specifically in CD4+ T cells prevented ANG II-induced hypertension. Therefore, RGS2 expression in CD4+ T cells plays a critical role in the development of HTN.

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