Iwase M, Bishop S P, Uechi M, Vatner D E, Shannon R P, Kudej R K, Wight D C, Wagner T E, Ishikawa Y, Homcy C J, Vatner S F
Department of Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston, Mass., USA.
Circ Res. 1996 Apr;78(4):517-24. doi: 10.1161/01.res.78.4.517.
To study the physiological effect of the overexpression of myocardial Gsalpha (protein levels increased by approximately threefold in transgenic mice), we examined the responsiveness to sympathomimetic amines by echocardiography (9 MHz) in five transgenic mice and five control mice (both 10.3 +/- 0.2 months old). Myocardial contractility in transgenic mice, as assessed by left ventricular (LV) fractional shortening (LVFS) and LV ejection fraction (LVEF) was not different from that of control mice at baseline (LVFS, 40 +/- 3% versus 36 +/- 2%; LVEF, 78 +/- 3% versus 74 +/- 3%). LVFS and LVEF values in transgenic mice during isoproterenol (ISO, 0.02 micrograms/kg per minute) infusion were higher than the values in control mice (LVFS, 68 +/- 4% versus 48 +/- 3%; LVEF, 96 +/- 1% versus 86 +/- 3%; P < .05). Norepinephrine (NE, 0.2 micrograms/kg per minute) infusion also increased LVFS and LVEF in transgenic mice more than in control mice (LVFS, 59 +/- 4% versus 47 +/- 3%; LVEF, 93 +/- 2% versus 85 +/- 3%; P < .05). Heart rates of transgenic mice were higher than those of control mice during ISO and NE infusion. In three transgenic mice with heart rates held constant, LV dP/dt rose by 33 +/- 2% with ISO (0.02 micrograms/kg per minute) and by only 13 +/- 2% in three wild-type control mice (P < .01). NE (0.1 micrograms/kg per minute) also induced a greater effect on LV dP/dt in the three transgenic mice with heart rates held constant compared with three wild-type control mice (65 +/ 8% versus 28 +/- 4%, P < .05). Pathological and histological analyses of older transgenic mouse hearts (16.0 +/- 0.8 months old) revealed hypertrophy, degeneration, atrophy of cells, and replacement fibrosis reflected by significant increases in collagen volume in the subendocardium (5.2 +/- 1.4% versus 1.2 +/- 0.3%, P < .05) and in the cross-sectional area of myocytes (298 +/- 29 versus 187 +/- 12 micron2, P < .05) compared with control mouse hearts. These results suggest that Gsalpha overexpression enhances the efficacy of the beta-adrenergic receptor-Gs-adenylyl cyclase signaling pathway. This in turn leads to augmented inotropic and chronotropic responses to endogenous sympathetic stimulation. This action over the life of the animal results in myocardial damage characterized by cellular degeneration, necrosis, and replacement fibrosis, with the remaining cells undergoing compensatory hypertrophy. As a model, this transgenic mouse offers new insights into the mechanisms of cardiomyopathy and heart failure and provides a new tool for their study.
为研究心肌Gsα过表达（转基因小鼠中蛋白质水平增加约三倍）的生理效应，我们通过超声心动图（9MHz）检测了5只转基因小鼠和5只对照小鼠（均为10.3±0.2月龄）对拟交感胺的反应性。通过左心室（LV）缩短分数（LVFS）和LV射血分数（LVEF）评估，转基因小鼠的心肌收缩力在基线时与对照小鼠无差异（LVFS，40±3%对36±2%；LVEF，78±3%对74±3%）。异丙肾上腺素（ISO，0.02微克/千克每分钟）输注期间，转基因小鼠的LVFS和LVEF值高于对照小鼠（LVFS，68±4%对48±3%；LVEF，96±1%对86±3%；P<0.05）。去甲肾上腺素（NE，0.2微克/千克每分钟）输注也使转基因小鼠的LVFS和LVEF增加幅度大于对照小鼠（LVFS，59±4%对47±3%；LVEF，93±2%对85±3%；P<0.05）。ISO和NE输注期间，转基因小鼠的心率高于对照小鼠。在三只心率保持恒定的转基因小鼠中，ISO（0.02微克/千克每分钟）使LV dP/dt升高33±2%，而三只野生型对照小鼠仅升高13±2%（P<0.01）。NE（0.1微克/千克每分钟）对三只心率保持恒定的转基因小鼠LV dP/dt的影响也大于三只野生型对照小鼠（65±8%对 28±4%，P<0.05）。对老年转基因小鼠心脏（16.0±0.8月龄）的病理和组织学分析显示，与对照小鼠心脏相比，心内膜下胶原体积显著增加（5.2±1.4%对1.2±0.3%，P<0.05）以及心肌细胞横截面积增加（298±29对187±12平方微米，P<0.05），反映出细胞肥大、变性、萎缩和替代性纤维化。这些结果表明，Gsα过表达增强了β-肾上腺素能受体-Gs-腺苷酸环化酶信号通路的效能。这进而导致对内源性交感神经刺激的变力性和变时性反应增强。这种作用在动物生命过程中导致心肌损伤，其特征为细胞变性、坏死和替代性纤维化，其余细胞发生代偿性肥大。作为一种模型，这种转基因小鼠为心肌病和心力衰竭的机制提供了新的见解，并为其研究提供了新的工具。
