G12-G13–LARG–mediated signaling in vascular smooth muscle is required for salt-induced hypertension

Wirth, Angela; Benyó, Zoltán; Lukasova, Martina; Leutgeb, Barbara; Wettschureck, Nina; Gorbey, Stefan; Őrsy, Petra; Horváth, Béla; Maser-Gluth, Christiane; Greiner, Erich F.; Lemmer, Björn; Schütz, Günther; Gutkind, J. Silvio; Offermanns, Stefan

doi:10.1038/nm1666

Cited by 601 publications

(695 citation statements)

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“…Ptger3 flox/flox mice (Jackson Laboratories) were used for the conditional deletion experiment and also served as a source for global EP 3 receptor-deficient mice after crossing with EIIa-Cre (45) animals. The inducible SMMHC-CreER T2 line has been described previously (33), and villin-Cre mice were from Jackson Laboratories. Cre activity was induced by intraperitoneal administration of tamoxifen (50 μL of a 20 mg/mL solution in miglyol per mouse) for 5 consecutive days.…”

Section: Methodsmentioning

confidence: 99%

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP ₃ receptors

Tunaru

Althoff

Nüsing

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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174

127

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Castor oil is one of the oldest drugs. When given orally, it has a laxative effect and induces labor in pregnant females. The effects of castor oil are mediated by ricinoleic acid, a hydroxylated fatty acid released from castor oil by intestinal lipases. Despite the wide-spread use of castor oil in conventional and folk medicine, the molecular mechanism by which ricinoleic acid acts remains unknown. Here we show that the EP 3 prostanoid receptor is specifically activated by ricinoleic acid and that it mediates the pharmacological effects of castor oil. In mice lacking EP 3 receptors, the laxative effect and the uterus contraction induced via ricinoleic acid are absent. Although a conditional deletion of the EP 3 receptor gene in intestinal epithelial cells did not affect castor oil-induced diarrhea, mice lacking EP 3 receptors only in smooth-muscle cells were unresponsive to this drug. Thus, the castor oil metabolite ricinoleic acid activates intestinal and uterine smooth-muscle cells via EP 3 prostanoid receptors. These findings identify the cellular and molecular mechanism underlying the pharmacological effects of castor oil and indicate a role of the EP 3 receptor as a target to induce laxative effects.G-protein coupled receptor | peristalsis | Ricinus communis | PGE 2

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Section: Methodsmentioning

confidence: 99%

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP ₃ receptors

Tunaru

Althoff

Nüsing

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

174

127

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“…A smooth muscle-specific deletion of RISP was generated by crossing a tamoxifen-inducible Cre recombinase driven by the SMC myosin heavy chain promoter (SMC-MHC-Cre) (33) with an RISP flox/flox mouse to generate an SMC-MHC-Cre/RISP flox/flox mouse in a mixed genetic background. See online supplement for expansion of this method.…”

Section: Conditional Smooth Muscle Risp Knockout Mousementioning

confidence: 99%

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

Waypa

Marks

Guzy

et al. 2013

Am J Respir Crit Care Med

138

145

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Rationale: The role of reactive oxygen species (ROS) signaling in the O 2 sensing mechanism underlying acute hypoxic pulmonary vasoconstriction (HPV) has been controversial. Although mitochondria are important sources of ROS, studies using chemical inhibitors have yielded conflicting results, whereas cellular models using genetic suppression have precluded in vivo confirmation. Hence, genetic animal models are required to test mechanistic hypotheses. Objectives: We tested whether mitochondrial Complex III is required for the ROS signaling and vasoconstriction responses to acute hypoxia in pulmonary arteries (PA). Methods: A mouse permitting Cre-mediated conditional deletion of the Rieske iron-sulfur protein (RISP) of Complex III was generated. Adenoviral Cre recombinase was used to delete RISP from isolated PA vessels or smooth muscle cells (PASMC). Measurements and Main Results: In PASMC, RISP depletion abolished hypoxia-induced increases in ROS signaling in the mitochondrial intermembrane space and cytosol, and it abrogated hypoxia-induced increases in [Ca 21 ] i . In isolated PA vessels, RISP depletion abolished hypoxia-induced ROS signaling in the cytosol. Breeding the RISP mice with transgenic mice expressing tamoxifen-activated Cre in smooth muscle permitted the depletion of RISP in PASMC in vivo. Precision-cut lung slices from those mice revealed that RISP depletion abolished hypoxia-induced increases in [Ca 21 ] i of the PA. In vivo RISP depletion in smooth muscle attenuated the acute hypoxia-induced increase in right ventricular systolic pressure in anesthetized mice. Conclusions: Acute hypoxia induces superoxide release from Complex III of smooth muscle cells. These oxidant signals diffuse into the cytosol and trigger increases in [Ca 21 ] i that cause acute hypoxic pulmonary vasoconstriction.Keywords: oxygen sensing; Rieske iron-sulfur protein; reactive oxygen species; roGFP; hypoxic pulmonary vasoconstrictionIn the lung, alveolar hypoxia triggers acute constriction of small pulmonary arteries (PA), a response termed hypoxic pulmonary vasoconstriction (HPV). This response is recapitulated in cultured PA smooth muscle cells (PASMC), indicating that the oxygen-sensing mechanism underlying HPV is intrinsic to the PASMC (1-12). Our previous work has implicated increases in reactive oxygen species (ROS) signaling during hypoxia (9,10, 12). Previous studies using mitochondrial inhibitors and mitochondria-deficient (r 0 ) cells suggested that the electron transport chain (ETC) is required for hypoxia-induced ROS signaling in the pulmonary circulation (9, 11-18). We subsequently assessed ROS signaling in hypoxic PASMC using roGFP, a thiol-containing, redox-sensitive reporter (19-23) targeted to compartments within mitochondria or the cytosol (10). Unlike other methods (24-26), this targeted approach permitted the differentiation of hypoxia-induced ROS changes between mitochondrial subcompartments. During hypoxia, increased oxidation was detected in the mitochondrial intermembrane space (IMS) and the cytoso...

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“…32 Moreover, a tamoxifen-inducible, smooth-muscle myosin heavy-chain promoter-driven Cre will be of utility to inactivate SRF at any time during embryonic or postnatal development. 59 SRF AND SKELETAL MUSCLE SYSTEM DISEASE The rostral-caudal segmentation of the paraxial mesoderm leads to the formation of somites where a subset of precursor cells are fated to become skeletal muscle. 60 Although Sm22a is active during early somitogenesis, there was no reported embryonic phenotype in SRF-null somites, probably because of the early manifestation of cardiac/SMC defects.…”

Section: Blood Vesselsmentioning

confidence: 99%

Role of serum response factor in the pathogenesis of disease

Miano

2010

Laboratory Investigation

120

100

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Serum response factor (SRF) is a ubiquitously expressed transcription factor that binds to a DNA cis element known as the CArG box, which is found in the proximal regulatory regions of over 200 experimentally validated target genes. Genetic deletion of SRF is incompatible with life in a variety of animals from different phyla. In mice, loss of SRF throughout the early embryo results in gastrulation defects precluding analyses in individual organ systems. Genetic inactivation studies using conditional or inducible promoters directing the expression of the bacteriophage Cre recombinase have shown a vital role for SRF in such cellular processes as contractility, cell migration, synaptic activity, inflammation, and cell survival. A growing number of experimental and human diseases are associated with changes in SRF expression, suggesting that SRF has a role in the pathogenesis of disease. This review summarizes data from experimental model systems and human pathology where SRF expression is either deliberately or naturally altered. Genomic DNA is a quaternary code comprising proteincoding and non-protein-coding sequences. While the protein-coding sequences are well-defined and increasingly understood, we are only beginning to elucidate the hidden information within the vast landscape of the non-proteincoding sequences. The field of comparative genomics has facilitated the identification of transcription factor-binding sites (TFBS) and microRNAs (miRs), which, aside from repetitive DNA sequences, are among the more easily decipherable non-protein-coding sequences in the human genome. Together, TFBS and miRs have essential roles in cell fate determination and cellular homeostasis of most life forms. Sequence variations (eg, single-nucleotide polymorphisms, SNPs) in the TFBS, miRs, and miR target sequences alter gene/protein expression and thus disturb homeostasis leading to disease. 1-4 A major imperative, therefore, is decoding the non-protein-coding genome relating to gene regulation to gain a full understanding of how DNA-binding transcription factors and the estimated one million or more TFBS direct normal biological processes.Serum response factor (SRF) is the founding member of the MADS-box family of transcription factors 5 and is one of the best understood DNA-binding proteins in the human proteome. The DNA-binding properties of SRF and its molecular cloning were first defined in the laboratory of Richard Treisman. 6,7 SRF has relatively low intrinsic transcriptional activity, but its interaction with over 60 cofactors confers strong transactivation potential in a cell-and context-specific manner. At least two major signaling pathways converge upon SRF to direct the programs of gene expression. 8,9 The classic pathway involves growth factor stimulation and mitogen-activated protein kinase signaling leading to the phosphorylation of the SRF cofactor, ELK1, and the activation of growth-related genes. 10,11 The second regulatory pathway occurs through Rho-dependent changes in actin dynamics. 12 In this pathway, si...

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G12-G13–LARG–mediated signaling in vascular smooth muscle is required for salt-induced hypertension

Cited by 601 publications

References 28 publications

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP ₃ receptors

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP ₃ receptors

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

Role of serum response factor in the pathogenesis of disease

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G12-G13–LARG–mediated signaling in vascular smooth muscle is required for salt-induced hypertension

Cited by 601 publications

References 28 publications

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP 3 receptors

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP 3 receptors

Superoxide Generated at Mitochondrial Complex III Triggers Acute Responses to Hypoxia in the Pulmonary Circulation

Role of serum response factor in the pathogenesis of disease

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Product

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About

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP ₃ receptors

Castor oil induces laxation and uterus contraction via ricinoleic acid activating prostaglandin EP ₃ receptors