Imai Hajime, Numaguchi Yasushi, Ishii Masakazu, Kubota Ryuji, Yokouchi Kazuhiko, Ogawa Yasuhiro, Kondo Takahisa, Okumura Kenji, Murohara Toyoaki
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Atherosclerosis. 2007 Dec;195(2):322-32. doi: 10.1016/j.atherosclerosis.2007.01.010. Epub 2007 Feb 14.
Prostacyclin (PGI(2)) is a potent ligand of peroxisome proliferator-activated receptor delta (PPAR delta) that regulates cell growth and differentiation. The aim of this study was to elucidate how endogenous PGI(2) overexpression affects the expressions of PPAR delta and mitogen-activated protein kinases (MAPKs) in the development of neointimal formation in experimental angioplasty with adenovirus-mediated PGI(2) synthase (Ad-PGIS) gene transfer.
In human aortic smooth muscle cells, protein blotting analysis showed that PGI(2) overproduction decreased the levels of phosphorylated p38 MAPK (P-p38 MAPK) (2.0-fold versus 0.83-fold relative to control). Immunohistochemical analysis in balloon-injured arteries revealed diffuse expression of PPAR delta in the neointima of control vessels, with no expression in uninjured vessels. The level of PPAR delta expression was lower in Ad-PGIS-treated arteries than in control vessels, with the PPAR delta localized in the neointima adjacent to endothelium. Staining of P-p38 MAPK showed a similar pattern to PPAR delta among the three groups. Morphometric analysis at day 14 revealed that Ad-PGIS reduced the intima-to-media ratio by up to 59%.
Ad-PGIS gene transfer reduced PPAR delta expression and inhibited neointimal formation after balloon injury in accordance with the reduction in the phosphorylation of p38 MAPK.
前列环素（PGI₂）是过氧化物酶体增殖物激活受体δ（PPARδ）的一种强效配体，可调节细胞生长和分化。本研究旨在阐明在腺病毒介导的PGI₂合酶（Ad-PGIS）基因转移的实验性血管成形术中，内源性PGI₂过表达如何影响新生内膜形成过程中PPARδ和丝裂原活化蛋白激酶（MAPK）的表达。
在人主动脉平滑肌细胞中，蛋白质印迹分析表明，PGI₂过量产生降低了磷酸化p38 MAPK（P-p38 MAPK）的水平（相对于对照组，分别为2.0倍和0.83倍）。球囊损伤动脉的免疫组织化学分析显示，PPARδ在对照血管的新生内膜中呈弥漫性表达，而在未损伤血管中无表达。Ad-PGIS处理的动脉中PPARδ的表达水平低于对照血管，PPARδ定位于靠近内皮的新生内膜中。P-p38 MAPK的染色在三组中显示出与PPARδ相似的模式。第14天的形态计量分析显示，Ad-PGIS使内膜与中膜比值降低了59%。
Ad-PGIS基因转移降低了PPARδ的表达，并根据p38 MAPK磷酸化的降低抑制了球囊损伤后的新生内膜形成。
