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

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570669/
关键词：
angiotensin receptor cardiac hypertrophy coronary artery AT1 receptor blocker fibrosis signal transducer phosphatase アポトーシス Aortic banding アンジオテンシンII受容体 AT2受容体欠損マウス Aortic Banding 心筋細胞

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.

主动脉腹部结带引起心脏肥大，并伴有心脏重量、心肌细胞大小、冠状动脉厚度和冠状动脉血管周围纤维化的增加。 AT2受体缺陷（AT2KO）小鼠的心肌变化与野生型（WT）小鼠相似，但冠状动脉的变化更为夸张。缬沙坦是一种 AT 1 受体阻滞剂，可显着抑制 WT 和 AT2KO 小鼠的心脏重量和心肌细胞大小。缬沙坦对WT小鼠的冠状动脉增厚和血管周围纤维化有抑制作用，但对AT2KO小鼠的抑制作用较小。 TUNEL染色、单链DNA和Hoechst33342检测到细胞凋亡，冠状动脉和血管周围区域Bax表达增加。 AT2KO 小鼠中细胞凋亡变化减少，但 WT 小鼠中缬沙坦增加了细胞凋亡变化。从新生小鼠皮肤中分离和培养的成纤维细胞显示，血管紧张素 (Ang) II 可以增加胶原蛋白合成和 TIMP-1 表达。 Ang II 诱导的这些变化被缬沙坦抑制，但被 AT2 拮抗剂 PD123319 增强。 Ang II 抑制 AT1KO 小鼠中 IGF-1 诱导的胶原蛋白合成和 TIMT-1 表达的增加。将酪氨酸磷酸酶显性失活突变体 SHP-1 转染至成纤维细胞，可降低 Ang II 对 AT1KO 小鼠胶原蛋白合成的抑制作用。这些结果表明，AT2 受体刺激可抵消 AT 1 受体刺激的作用，从而抑制血管紧张素 II 的合成。心脏肥大时观察到冠状动脉增厚和血管周围纤维化的变化。