| First Author | De Silva TM | Year | 2017 |
| Journal | Hypertension | Volume | 70 |
| Issue | 3 | Pages | 559-565 |
| PubMed ID | 28674038 | Mgi Jnum | J:283427 |
| Mgi Id | MGI:6368389 | Doi | 10.1161/HYPERTENSIONAHA.117.09358 |
| Citation | De Silva TM, et al. (2017) Genetic Interference With Endothelial PPAR-gamma (Peroxisome Proliferator-Activated Receptor-gamma) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7. Hypertension 70(3):559-565 |
| abstractText | Pharmacological activation of PPAR-gamma (peroxisome proliferator-activated receptor-gamma) protects the vasculature. Much less is known on the cell-specific impact of PPAR-gamma when driven by endogenous ligands. Recently, we found that endothelial PPAR-gamma 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-gamma 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-kappaB (nuclear factor-kappa B essential modulator-binding domain peptide), or interleukin-6 (neutralizing antibody). In addition, we hypothesized that PPAR-gamma 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-gamma through sex-independent mechanisms, involving oxidant-inflammatory signaling and ROCK2 (Rho kinase). The study also provides the first evidence that endothelial PPAR-gamma interacts with angiotensin 1-7 responses. These critical roles for endothelial PPAR-gamma have implications for pathophysiology and therapeutic approaches for vascular disease. |
