Akazawa Hiroshi, Zou Yunzeng, Komuro Issei
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
Novartis Found Symp. 2006;274:20-31; discussion 31-40, 152-5, 272-6.
Angiotensin II (AII) type 1 (AT1) receptor plays a critical role in load-induced cardiac hypertrophy. We have recently found a novel mechanism of mechanical stress-induced activation of the AT1 receptor, which is independent of AII. Mechanical stretch did not activate ERKs in HEK293 cells and COS7 cells which had no AT1 receptor, but when AT1 receptor was overexpressed in these cells, stretch activated ERKs, Galphaq and JAK2. An AT1 receptor blocker, candesartan, inhibited stretch-induced activation of ERKs in these cells. Stretch also activated ERKs in COS7 cells expressing AT1 mutant which did not bind AII and in cardiac myocytes prepared from angiotensinogen null mice. Stretch did not activate ERKs in COS7 cells which overexpressed ETA receptor and beta-adrenergic receptor. Pressure overload induced cardiac hypertrophy in angiotensinogen null mice as well as in wild-type mice, which was significantly inhibited by candesartan. These results suggest that mechanical stress activates AT1 receptor independently of AII, which is inhibited by an inverse agonist candesartan.
血管紧张素II（AII）1型（AT1）受体在负荷诱导的心肌肥大中起关键作用。我们最近发现了一种机械应力诱导AT1受体激活的新机制，该机制独立于AII。机械牵张在没有AT1受体的HEK293细胞和COS7细胞中不激活细胞外信号调节激酶（ERK），但当在这些细胞中过表达AT1受体时，牵张可激活ERK、Gαq和Janus激酶2（JAK2）。一种AT1受体阻滞剂坎地沙坦可抑制这些细胞中牵张诱导的ERK激活。牵张也可激活不结合AII的AT1突变体表达的COS7细胞以及由血管紧张素原基因敲除小鼠制备的心肌细胞中的ERK。牵张在过表达内皮素A（ETA）受体和β-肾上腺素能受体的COS7细胞中不激活ERK。压力超负荷在血管紧张素原基因敲除小鼠以及野生型小鼠中均可诱导心肌肥大，而坎地沙坦可显著抑制这种肥大。这些结果表明，机械应力可独立于AII激活AT1受体，而反向激动剂坎地沙坦可抑制该激活过程。
