Genetic Interference With Endothelial PPAR-γ (Peroxisome Proliferator–Activated Receptor-γ) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1–7Novelty and Significance
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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 (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-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% (P<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.
- Received March 6, 2017.
- Revision received March 27, 2017.
- Accepted May 31, 2017.
- © 2017 American Heart Association, Inc.