Hu Chunyan, Lu Ko-Ting, Mukohda Masashi, Davis Deborah R, Faraci Frank M, Sigmund Curt D
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa;
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa; and Iowa City Veterans Affairs Healthcare System, Iowa City, Iowa.
Physiol Genomics. 2016 Feb;48(2):124-34. doi: 10.1152/physiolgenomics.00087.2015. Epub 2015 Nov 3.
The ligand activated nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) in the endothelium regulates vascular function and blood pressure (BP). We previously reported that transgenic mice (E-V290M) with selectively targeted endothelial-specific expression of dominant negative PPARγ exhibited endothelial dysfunction when treated with a high-fat diet, and exhibited an augmented pressor response to angiotensin II (ANG II). We hypothesize that interference with endothelial PPARγ would exacerbate ANG II-induced endothelial dysfunction. Endothelial function was examined in E-V290M mice infused with a subpressor dose of ANG II (120 ng·kg(-1)·min(-1)) or saline for 2 wk. ANG II infusion significantly impaired the responses to the endothelium-dependent agonist acetylcholine both in basilar and carotid arteries from E-V290M but not NT mice. This impairment was not due to increased BP, which was not significantly different in ANG II-infused E-V290M compared with NT mice. Superoxide levels, and expression of the pro-oxidant Nox2 gene was elevated, whereas expression of the anti-oxidant genes Catalase and SOD3 decreased in carotid arteries from ANG II-infused E-V290M mice. Increased p65 and decreased Iκ-Bα suggesting increased NF-κB activity was also observed in aorta from ANG II-infused E-V290M mice. The responses to acetylcholine were significantly improved both in basilar and carotid arteries after treatment with Tempol (1 mmol/l), a scavenger of superoxide. These findings provide evidence that interference with endothelial PPARγ accelerates ANG II-mediated endothelial dysfunction both in cerebral and conduit arteries through an oxidative stress-dependent mechanism, suggesting a role for endothelial PPARγ in protecting against ANG II-induced endothelial dysfunction.
内皮细胞中的配体激活核受体过氧化物酶体增殖物激活受体γ（PPARγ）调节血管功能和血压（BP）。我们之前报道，具有选择性靶向内皮特异性表达显性负性PPARγ的转基因小鼠（E-V290M）在高脂饮食处理时表现出内皮功能障碍，并对血管紧张素II（ANG II）表现出增强的升压反应。我们假设干扰内皮PPARγ会加剧ANG II诱导的内皮功能障碍。对输注亚升压剂量的ANG II（120 ng·kg⁻¹·min⁻¹）或生理盐水2周的E-V290M小鼠的内皮功能进行了检测。ANG II输注显著损害了E-V290M小鼠基底动脉和颈动脉对内皮依赖性激动剂乙酰胆碱的反应，但对NT小鼠无此影响。这种损害并非由于血压升高，输注ANG II的E-V290M小鼠与NT小鼠相比，血压无显著差异。在输注ANG II的E-V290M小鼠的颈动脉中，超氧化物水平升高，促氧化剂Nox2基因的表达增加，而抗氧化基因过氧化氢酶和超氧化物歧化酶3（SOD3）的表达下降。在输注ANG II的E-V290M小鼠的主动脉中也观察到p65增加和Iκ-Bα减少，提示核因子κB（NF-κB）活性增加。用超氧化物清除剂Tempol（1 mmol/l）处理后，基底动脉和颈动脉对乙酰胆碱的反应均显著改善。这些发现提供了证据，表明干扰内皮PPARγ通过氧化应激依赖性机制加速ANG II介导的脑动脉和传导动脉的内皮功能障碍，提示内皮PPARγ在预防ANG II诱导的内皮功能障碍中发挥作用。
