Meyer M, Trost S U, Bluhm W F, Knot H J, Swanson E, Dillmann W H
Department of Medicine, University of California, San Diego, California 92093, USA.
Am J Physiol Heart Circ Physiol. 2001 May;280(5):H2046-52. doi: 10.1152/ajpheart.2001.280.5.H2046.
Sarcoplasmic reticulum (SR)-mediated Ca(2+) sequestration and release are important determinants of cardiac contractility. In end-stage heart failure SR dysfunction has been proposed to contribute to the impaired cardiac performance. In this study we tested the hypothesis that a targeted interference with SR function can be a primary cause of contractile impairment that in turn might alter cardiac gene expression and induce cardiac hypertrophy. To study this we developed a novel animal model in which ryanodine, a substance that alters SR Ca(2+) release, was added to the drinking water of mice. After 1 wk of treatment, in vivo hemodynamic measurements showed a 28% reduction in the maximum speed of contraction (+dP/dt(max)) and a 24% reduction in the maximum speed of relaxation (-dP/dt(max)). The slowing of cardiac relaxation was confirmed in isolated papillary muscles. The late phase of relaxation expressed as the time from 50% to 90% relaxation was prolonged by 22%. After 4 wk of ryanodine administration the animals had developed a significant cardiac hypertrophy that was most prominent in both atria (right atrium +115%, left atrium +100%, right ventricle +23%, and left ventricle +13%). This was accompanied by molecular changes including a threefold increase in atrial natriuretic factor mRNA and a sixfold increase in beta-myosin heavy chain mRNA. Sarcoplasmic endoplasmic reticulum Ca(2+) mRNA was reduced by 18%. These data suggest that selective impairment of SR function in vivo can induce changes in cardiac gene expression and promote cardiac growth.
肌浆网（SR）介导的钙离子摄取和释放是心脏收缩力的重要决定因素。在终末期心力衰竭中，有人提出SR功能障碍会导致心脏功能受损。在本研究中，我们测试了以下假设：对SR功能的靶向干扰可能是收缩功能受损的主要原因，进而可能改变心脏基因表达并诱发心脏肥大。为了研究这一点，我们开发了一种新型动物模型，将能改变SR钙离子释放的物质——雷诺丁添加到小鼠的饮用水中。治疗1周后，体内血流动力学测量显示，收缩最大速度（+dP/dt(max)）降低了28%，舒张最大速度（-dP/dt(max)）降低了24%。在离体乳头肌中也证实了心脏舒张减慢。以从50%舒张到90%舒张的时间表示的舒张后期延长了22%。给予雷诺丁4周后，动物出现了明显的心脏肥大，在两个心房中最为显著（右心房增加115%，左心房增加100%，右心室增加23%，左心室增加13%）。这伴随着分子变化，包括心房利钠因子mRNA增加三倍，β-肌球蛋白重链mRNA增加六倍。肌浆内质网钙离子mRNA减少了18%。这些数据表明，体内SR功能的选择性损害可诱导心脏基因表达的变化并促进心脏生长。
