Vascular and central activation of Peroxisome Proliferator-Activated Receptor-β attenuates angiotensin II-induced hypertension. Role of RGS-5.
(2016) The Journal of Pharmacology and Experimental Therapeutics — Vol. 358, n° 1, p. 151-163 (2016)
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VascularandcentralactivationofPeroxisomeProliferator-ActivatedReceptor-βattenuatesangiotensinII-inducedhypertensionRoleofRGS-5.pdf
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- Activation of peroxisome proliferator-activated receptor-β/δ (PPARβ) lowers blood pressure in genetic and mineralocorticoid-induced hypertension. Regulators of G-protein-coupled receptor signaling (RGS)5 protein, which interfere in angiotensin (Ang)II 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 5 groups, control-mice, PPARβ agonist GW0742-treated-mice, AngII-infused-mice, GW0742-treated-AngII-infused-mice, and AngII-infused-mice-treated with GW0742 plus PPARβ antagonist GSK0660, and were followed for 3 weeks. GW0742 prevented the raise in both arterial blood pressure and plasma noradrenaline levels, and the higher reduction on blood pressure after ganglionic blockade, whereas 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 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 anti-hypertensive 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 up-regulation.
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Romero, M., Jimenez, R., Toral, M., Leon-Gomez, E., Gomez-Guzman, M., Sanchez, M., Zarzuelo, M. J., Rodriguez-Gomez, I., Rath, G., Tamargo, J., Perez-Vizcaino, F., Dessy, C., & Duarte, J. (2016). Vascular and central activation of Peroxisome Proliferator-Activated Receptor-β attenuates angiotensin II-induced hypertension. Role of RGS-5. The Journal of Pharmacology and Experimental Therapeutics, 358(1), 151-163. https://doi.org/10.1124/jpet.116.233106 (Original work published 2016)