Role of angiotensin II receptor subtypes on cardiovascular remodeling induced by aortic banding

血管紧张素II受体亚型在主动脉束带诱导的心血管重塑中的作用

基本信息

批准号：
14570669
负责人：
IWAI Masaru
金额：
$ 1.86万
依托单位：
Ehime University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

The banding of abdominal portion of aorta induced cardiac hypertrophy accompanied with the increase in heart weight, cardiomyocyte size, coronary artery thickness and perivascular fibrosis of coronary artery. In AT2 receptor deficient (AT2KO) mice, the changes of cardiac muscle were similar to, but the changes of coronary artery were more exaggerated than in wild type (WT) mice. Valsartan, an AT 1 receptor blocker, significantly inhibited the heart weight and cardiomyocyte size both in WT and AT2KO mice. The coronary artery thickening and perivascular fibrosis were inhibited by valsartan in WT mice, but the inhibitory actions of valsartan were smaller in AT2KO mice. Apoptosis detected by TUNEL staining, single stand DNA and Hoechst33342, and Bax expression was increased in coronary artery and perivascular region. The apoptotic changes were decreased in AT2KO mice but increased by valsartan in WT mice. Fibroblasts isolated and cultured from neonatal mice skin showed an increase in collagen synthesis and TIMP-1 expression by angiotensin (Ang) II. These changes induced by Ang II were inhibited by valsartan but enhanced by AT2 antagonist, PD123319. Ang II inhibited the increase in collagen synthesis and TIMT-1 expression induced by IGF-1 in AT1KO mice. Transfection of dominant negative mutant of a tyrosine phsphatase, SHP-1, into fibroblast decreased the inhibitory actions of Ang II on collagen synthesis in AT1KO mice.These resukts suggest that AT2 receptor stimulation counter acts on the effects of AT 1 receptor stimulation to inhibit the changes of coronary artery thickening and perivascular fibrosis observed in cardiac hypertrophy.

主动脉诱导心脏肥大的腹部部分的带伴随着心脏体重的增加，心肌细胞大小，冠状动脉厚度和冠状动脉周围纤维化。在AT2受体缺乏（AT2KO）小鼠中，心肌的变化类似，但是冠状动脉的变化比野生型（WT）小鼠更夸张。瓦尔萨坦（Valsartan）是一种AT 1受体阻滞剂，在WT和AT2KO小鼠中都显着抑制了心脏重量和心肌细胞的大小。瓦尔萨坦在WT小鼠中抑制了冠状动脉增厚和血管周围纤维化，但是在AT2KO小鼠中，瓦尔萨坦的抑制作用较小。通过TUNEL染色，单架DNA和HOECHST33342检测到的凋亡，并且在冠状动脉和血管周围区域增加了BAX表达。 AT2KO小鼠的凋亡变化减少，但在WT小鼠中瓦尔萨坦增加了。从新生小鼠皮肤分离并培养的成纤维细胞表明，血管紧张素（ANG）II的胶原蛋白合成和TIMP-1表达增加。瓦尔萨坦抑制了Ang II引起的这些变化，但AT2拮抗剂PD123319增强了这些变化。 ANG II抑制了IGF-1在AT1KO小鼠中诱导的胶原蛋白合成和TIMT-1表达的增加。将酪氨酸pHSPHATAPES SHP-1的显性负突变体转染到成纤维细胞中减少了ANG II对AT1KO小鼠中胶原蛋白合成的抑制作用。这些复位表明AT2受体刺激对1受体刺激的作用可抑制对抗激素的果实杂质的变化对抗激素的变化的作用。