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

主动脉腹段捆扎引起心肌肥厚，心脏重量增加，心肌细胞增大，冠状动脉厚度增加，冠状动脉血管周围纤维化。AT2受体缺陷（AT2KO）小鼠心肌的变化与野生型（WT）小鼠相似，但冠状动脉的变化比野生型（WT）小鼠更为夸张。缬沙坦是一种AT 1受体阻滞剂，在WT和AT2KO小鼠中均能显著抑制心脏重量和心肌细胞大小。缬沙坦对WT小鼠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stand DNA和Hoechst33342检测细胞凋亡，冠状动脉和血管周围区Bax表达升高。AT2KO小鼠的细胞凋亡变化减少，缬沙坦使WT小鼠的细胞凋亡变化增加。从新生小鼠皮肤中分离和培养成纤维细胞，血管紧张素（Ang） II诱导胶原合成和TIMP-1表达增加。缬沙坦抑制了Ang II诱导的这些变化，但AT2拮抗剂PD123319增强了这些变化。Ang II抑制IGF-1诱导的AT1KO小鼠胶原合成和TIMT-1表达的增加。将酪氨酸磷酸酶的显性阴性突变体SHP-1转染成纤维细胞，可降低Ang II对AT1KO小鼠胶原合成的抑制作用。提示AT2受体刺激拮抗作用于at1受体刺激，抑制心肌肥厚时冠状动脉增厚和血管周围纤维化的改变。

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.