Roth David M, Bayat Hamed, Drumm Jeffrey D, Gao Mei Hua, Swaney James S, Ander Aziz, Hammond H Kirk
VA San Diego Healthcare System, San Diego, CA 92161, USA.
Circulation. 2002 Apr 23;105(16):1989-94. doi: 10.1161/01.cir.0000014968.54967.d3.
To test the hypothesis that increased cardiac adenylyl cyclase type VI (AC(VI)) content, which results in increased cAMP generation, would increase survival in cardiomyopathy, we crossbred mice with Gq-associated cardiomyopathy and those with cardiac-directed expression of AC(VI). We also assessed myocardial hypertrophy after prolonged cardiac expression of Gq versus coexpression of Gq and AC(VI).
Three experimental groups, Gq/AC (double positive), Gq, and control (double negative), were studied. Survival was increased by cardiac-directed expression of AC(VI) (P<0.0001), and Gq/AC mice had survival rates indistinguishable from control mice. Myocardial hypertrophy developed in older Gq mice but was abrogated by cardiac expression of AC(VI), as documented by the ratio of ventricular weight to tibial length (Gq, 11.93+/-0.99 mg/mm, n=11; Gq/AC, 8.00+/-0.73 mg/mm, n=9; P<0.01) and by left ventricular cardiac myocyte size (Gq, 2800+/-254 microm2, n=4; Gq/AC, 1721+/-166 microm2, n=5; P<0.01). Hearts of Gq mice were dilated, and function was impaired. Concurrent expression of AC reduced end-diastolic diameter (Gq, 4.20+/-0.15 mm, n=12; Gq/AC, 3.68+/-0.12 mm, n=7; P<0.05) and increased fractional shortening (Gq, 32+/-1%, n=12; Gq/AC, 41+/-2%, n=7; P<0.001). Cardiac myocytes from Gq/AC mice showed increased forskolin-stimulated cAMP production (Gq, 3.8+/-1.3 fmol/cell, n=5; Gq/AC, 10.7+/-2.6 fmol/cell, n=6; P<0.02), documenting increased AC function.
Cardiac-directed expression of AC(VI) restores myocyte AC function, improves heart function, increases cAMP generation, abrogates myocardial hypertrophy, and increases survival in Gq cardiomyopathy.
为验证以下假说，即心脏中VI型腺苷酸环化酶（AC(VI)）含量增加会导致环磷酸腺苷（cAMP）生成增加，进而提高心肌病小鼠的生存率，我们将患有与Gq相关心肌病的小鼠与心脏定向表达AC(VI)的小鼠进行杂交。我们还评估了长期心脏表达Gq与共表达Gq和AC(VI)后心肌肥大的情况。
研究了三个实验组，即Gq/AC（双阳性）、Gq和对照组（双阴性）。心脏定向表达AC(VI)可提高生存率（P<0.0001），Gq/AC小鼠的生存率与对照小鼠无显著差异。老年Gq小鼠出现心肌肥大，但AC(VI)的心脏表达可消除这种肥大，这通过心室重量与胫骨长度之比得到证实（Gq组，11.93±0.99 mg/mm，n = 11；Gq/AC组，8.00±0.73 mg/mm，n = 9；P<0.01），以及左心室心肌细胞大小（Gq组，2800±254 μm2，n = 4；Gq/AC组，1721±166 μm2，n = 5；P<0.01）。Gq小鼠的心脏扩张，功能受损。AC的共表达可减小舒张末期直径（Gq组，4.20±0.15 mm，n = 12；Gq/AC组，3.68±0.12 mm，n = 7；P<0.05）并增加缩短分数（Gq组，32±1%，n = 12；Gq/AC组，41±2%，n = 7；P<0.001）。Gq/AC小鼠的心肌细胞显示福斯可林刺激的cAMP生成增加（Gq组，3.8±1.3 fmol/细胞，n = 5；Gq/AC组，10.7±2.6 fmol/细胞，n = 6；P<0.02），证明AC功能增强。
心脏定向表达AC(VI)可恢复心肌细胞AC功能，改善心脏功能，增加cAMP生成，消除心肌肥大，并提高Gq心肌病小鼠的生存率。
