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Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator-Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7
Journal article   Open access   Peer reviewed

Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator-Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7

T Michael De Silva, Chunyan Hu, Dale A Kinzenbaw, Mary L Modrick, Curt D Sigmund and Frank M Faraci
Hypertension (Dallas, Tex. 1979), Vol.70(3), pp.559-565
09/2017
DOI: 10.1161/HYPERTENSIONAHA.117.09358
PMCID: PMC5552422
PMID: 28674038
url
https://doi.org/10.1161/HYPERTENSIONAHA.117.09358View
Published (Version of record) Open Access

Abstract

Pharmacological activation of PPAR-γ (peroxisome proliferator-activated receptor-γ) protects the vasculature. Much less is known on the cell-specific impact of PPAR-γ when driven by endogenous ligands. Recently, we found that endothelial PPAR-γ protects against angiotensin II-induced endothelial dysfunction. Here, we explored that concept further examining whether effects were sex dependent along with underlying mechanisms. We studied mice expressing a human dominant-negative mutation in PPAR-γ driven by the endothelial-specific vascular cadherin promoter (E-V290M), using nontransgenic littermates as controls. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of carotid arteries from nontransgenic and E-V290M mice. Incubation of isolated arteries with angiotensin II (1 nmol/L) overnight had no effect in nontransgenic, but reduced responses to acetylcholine by about 50% in male and female E-V290M mice ( <0.05). Endothelial function in E-V290M mice was restored to normal by inhibitors of superoxide (tempol), NADPH oxidase (VAS-2870), Rho kinase (Y-27632), ROCK2 (SLX-2119), NF-κB (nuclear factor-kappa B essential modulator-binding domain peptide), or interleukin-6 (neutralizing antibody). In addition, we hypothesized that PPAR-γ may influence the angiotensin 1-7 arm of the renin-angiotensin system. In the basilar artery, dilation to angiotensin 1-7 was selectively reduced in E-V290M mice by >50% ( <0.05), an effect reversed by Y-27632. Thus, effects of angiotensin II are augmented by interference with endothelial PPAR-γ through sex-independent mechanisms, involving oxidant-inflammatory signaling and ROCK2 (Rho kinase). The study also provides the first evidence that endothelial PPAR-γ interacts with angiotensin 1-7 responses. These critical roles for endothelial PPAR-γ have implications for pathophysiology and therapeutic approaches for vascular disease.
 Amides Angiotensin I - metabolism Angiotensin I - pharmacology Angiotensin II - metabolism Angiotensin II - pharmacology Animals Animals, Genetically Modified Carotid Arteries - drug effects Carotid Arteries - metabolism Female Interleukin-6 - metabolism Male Mice NF-kappa B - metabolism Oxidative Stress - drug effects Oxidative Stress - physiology Peptide Fragments - metabolism Peptide Fragments - pharmacology PPAR gamma - metabolism Pyridines Renin-Angiotensin System - drug effects Renin-Angiotensin System - physiology Vascular Diseases - metabolism Vascular Diseases - physiopathology Vasoconstrictor Agents - pharmacology Vasodilation - drug effects Vasodilation - physiology

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