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

ABSTRACT: Pharmacological activation of PPAR-? (peroxisome proliferator-activated receptor-?) protects the vasculature. Much less is known on the cell-specific impact of PPAR-? when driven by endogenous ligands. Recently, we found that endothelial PPAR-? 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-? 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 (P<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-?B (nuclear factor-kappa B essential modulator-binding domain peptide), or interleukin-6 (neutralizing antibody). In addition, we hypothesized that PPAR-? 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% (P<0.05), an effect reversed by Y-27632. Thus, effects of angiotensin II are augmented by interference with endothelial PPAR-? through sex-independent mechanisms, involving oxidant-inflammatory signaling and ROCK2 (Rho kinase). The study also provides the first evidence that endothelial PPAR-? interacts with angiotensin 1-7 responses. These critical roles for endothelial PPAR-? have implications for pathophysiology and therapeutic approaches for vascular disease.

SUBMITTER: De Silva TM 

PROVIDER: S-EPMC5552422 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature