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

腹主动脉缩窄可引起心肌肥厚，心肌重量增加，心肌细胞体积增大，冠状动脉壁增厚，冠状动脉周围纤维化。AT 2受体缺陷型（AT 2KO）小鼠心肌的变化与野生型（WT）小鼠相似，但冠状动脉的变化较野生型（WT）小鼠明显。AT 1受体阻断剂Valsartan可显著抑制WT和AT 2 KO小鼠的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AT 2KO小鼠的抑制作用较小。TUNEL、单链DNA和Hoechst 33342染色检测冠状动脉及血管周围组织细胞凋亡，Bax表达增加。AT 2KO小鼠的凋亡变化减少，但在WT小鼠中缬沙坦增加。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增加胶原合成和TIMP-1表达。血管紧张素Ⅱ诱导的这些变化被缬沙坦抑制，但增强AT 2拮抗剂，PD 123319。Ang II抑制IGF-1诱导的AT 1 KO小鼠胶原合成和TIMT-1表达的增加。将酪氨酸磷酸酶显性失活突变体SHP-1转染成纤维细胞，可减弱Ang Ⅱ对AT 1 KO小鼠胶原合成的抑制作用，提示AT 2受体的激活可抵消AT 1受体的激活，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.