Swaney James S, Patel Hemal H, Yokoyama Utako, Lai N Chin, Spellman Matthew, Insel Paul A, Roth David M
Department of Pharmacology, University of California, San Diego, CA, USA.
Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H3216-20. doi: 10.1152/ajpheart.00739.2007. Epub 2007 Sep 14.
Myocardial infarction (MI) results in left ventricular remodeling (e.g., ventricular hypertrophy, dilatation, and fibrosis). Fibrosis contributes to increased myocardial stiffening, impaired ventricular filling and function, and reduced cardiac output. Adenylyl cyclase (AC) expression and activity are reduced in animal models of heart failure. Stimulation of AC can inhibit extracellular matrix production in isolated cardiac fibroblasts; however, a role for reduced AC expression and activity in fibrosis associated with cardiac remodeling after chronic MI has never been determined. We tested the hypothesis that AC expression and activity are reduced in cardiac fibroblasts after chronic (18 wk) MI. Rats underwent coronary artery ligation or sham surgery (control), and echocardiography was used to assess left ventricular remodeling 1, 3, 5, 7, 10, 12, and 18 wk after surgery. Cardiac fibroblasts were isolated from the noninfarcted myocardium and compared for differences in AC activity and collagen synthesis. End-diastolic dimension was increased [control: 0.76 +/- 0.02 cm and MI: 1.0 +/- 0.02 cm (means +/- SE), P < 0.001] and fractional shortening was decreased (control: 44 +/- 2% and MI: 17 +/- 2%, P < 0.001) in MI compared with control rats. Basal and forskolin-stimulated cAMP production were decreased by 90% and 93%, respectively, and AC5/6 expression was decreased 39% in fibroblasts isolated from MI rats compared with sham controls. Serum-stimulated collagen production was increased twofold and forskolin-mediated inhibition of collagen synthesis was reduced in fibroblasts from MI rats compared with controls. Our data demonstrate that AC expression and activity are reduced and collagen production is increased in cardiac fibroblasts of rats after MI.
心肌梗死（MI）会导致左心室重构（如心室肥厚、扩张和纤维化）。纤维化会导致心肌僵硬度增加、心室充盈和功能受损以及心输出量降低。在心力衰竭动物模型中，腺苷酸环化酶（AC）的表达和活性会降低。刺激AC可抑制分离的心脏成纤维细胞中细胞外基质的产生；然而，慢性心肌梗死后与心脏重构相关的纤维化中AC表达和活性降低所起的作用尚未确定。我们验证了慢性（18周）心肌梗死后心脏成纤维细胞中AC表达和活性降低的假说。对大鼠进行冠状动脉结扎或假手术（对照），并在术后1、3、5、7、10、12和18周使用超声心动图评估左心室重构。从非梗死心肌中分离出心脏成纤维细胞，并比较AC活性和胶原蛋白合成的差异。与对照大鼠相比，心肌梗死大鼠的舒张末期内径增加[对照：0.76±0.02 cm，心肌梗死：1.0±0.02 cm（平均值±标准误），P<0.001]，缩短分数降低（对照：44±2%，心肌梗死：17±2%，P<0.001）。与假手术对照组相比，从心肌梗死大鼠分离的成纤维细胞中，基础和福斯高林刺激的环磷酸腺苷（cAMP）生成分别降低了90%和93%，AC5/6表达降低了39%。与对照组相比，心肌梗死大鼠成纤维细胞中血清刺激的胶原蛋白生成增加了两倍，福斯高林介导的胶原蛋白合成抑制作用降低。我们的数据表明，心肌梗死后大鼠心脏成纤维细胞中AC表达和活性降低，胶原蛋白生成增加。
