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

Abstract

Activation of peroxisome proliferator-activated receptor-b/d (PPARb) 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 PPARb. The aim of the present study was to examine whether PPARb 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, PPARb agonist 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 PPARb 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 hyperresponsiveness to vasoconstrictors (AngII and endothelin-1) in AngIIinfused 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 PPARb activation in brain and vessels inhibiting AngII signaling as a result of RGS5 upregulation.

Maternal Metabolism and Vascular Adaptation in Pregnancy: The PPAR Link

“…These findings are consistent with earlier observations that PPARγ agonist treatment improves pregnancy outcome in preeclamptic rats [44], and provide the first genetic evidence for a direct control of blood pressure homeostasis by PPAR-mediated transcriptional regulation of RGS5. Furthermore, PPARβ agonist treatment also ameliorates AngII-induced experimental hypertension in mice via upregulation of RGS5 [78].…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…PPAR␤ activation attenuates the pressor and sympathoexcitatory actions of ANG II in the brain by inhibiting NADPH oxidase activity through a mechanism involving regulator of G protein signaling 5 (RGS5) (876). ANG II infusion decreases PPAR␥ DNA-binding activity in the brain, while activation of PPAR␥ in the brain blunts pressor response to systemically administered ANG II (1223).…”

Ligand-activated PPARδ inhibits angiotensin II-stimulated hypertrophy of vascular smooth muscle cells by targeting ROS

“…A recent study demonstrated that activated PPARδ attenuates Ang II-triggered hypertension by targeting regulator of G-protein-coupled receptor signaling 5 [19]. Based on this observation and our previous findings concerning the protective effects of PPARδ in the vasculature, we hypothesized that ligand-activated PPARδ may affect Ang II-induced vascular hypertrophy, a critical phenotype in hypertension.…”