Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor- Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5

Autor: Marta Toral, Manuel Gómez-Guzmán, María José Zarzuelo, Isabel Rodríguez-Gómez, Miguel Romero, Elvira Leon-Gomez, Juan Tamargo, Juan Duarte, Francisco Perez-Vizcaino, Rosario Jiménez, Chantal Dessy, Géraldine Rath, Manuel Sánchez
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Agonist
medicine.medical_specialty
medicine.drug_class
Peroxisome proliferator-activated receptor
Blood Pressure
Thiophenes
030204 cardiovascular system & hematology
GW0742
Norepinephrine
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Heart Rate
Internal medicine
medicine
Animals
Sulfones
PPAR-beta
Mesenteric arteries
Antihypertensive Agents
Pharmacology
chemistry.chemical_classification
NADPH oxidase
Dose-Response Relationship
Drug
biology
Angiotensin II
Mesenteric Arteries
Mice
Inbred C57BL
Thiazoles
030104 developmental biology
Endocrinology
Blood pressure
medicine.anatomical_structure
chemistry
Vasoconstriction
Hypertension
biology.protein
Molecular Medicine
Vascular Resistance
RGS Proteins
hormones
hormone substitutes
and hormone antagonists
Zdroj: Journal of Pharmacology and Experimental Therapeutics. 358:151-163
ISSN: 1521-0103
DOI: 10.1124/jpet.116.233106
Popis: Activation of peroxisome proliferator-activated receptor-β/δ (PPARβ) lowers blood pressure in genetic and mineralocorticoid-induced hypertension. Regulator of G-protein-coupled receptor signaling 5 (RGS5) protein, which interferes in angiotensin II (AngII) signaling, is a target gene to PPARβ The aim of the present study was to examine whether PPARβ activation in resistance arteries and brain tissues prevents the elevated blood pressure in AngII-induced hypertension and evaluate the role of RGS5 in this effect. C57BL/6J male mice were divided into five groups (control mice, PPARβ agonist [4-[[[2-[3-Fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742)-treated mice AngII-infused mice, GW0742-treated AngII-infused mice, and AngII-infused mice treated with GW0742 plus PPARβ antagonist 3-[[[2-Methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester (GSK0660)) and were followed for 3 weeks. GW0742 prevented the increase in both arterial blood pressure and plasma noradrenaline levels and the higher reduction of blood pressure after ganglionic blockade, whereas it reduced the mesenteric arterial remodeling and the hyper-responsiveness to vasoconstrictors (AngII and endothelin-1) in AngII-infused mice. These effects were accompanied by an inhibition of NADPH oxidase expression and activity in the brain. Gene expression profiling revealed a marked loss of brainstem and vascular RGS5 in AngII-infused mice, which was restored by GW0742. GW0742-induced effects were abolished by GSK0660. Small interfering RNA targeting RGS5 caused augmented contractile response to AngII in resistance mesenteric arteries and blunted the inhibitory effect of GW0742 on this response. In conclusion, GW0742 exerted antihypertensive effects, restoring sympathetic tone and vascular structure and function in AngII-infused mice by PPARβ activation in brain and vessels inhibiting AngII signaling as a result of RGS5 upregulation.
Databáze: OpenAIRE
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