Igarashi-Saito K, Tsutsui H, Yamamoto S, Takahashi M, Kinugawa S, Tagawa H, Usui M, Yamamoto M, Egashira K, Takeshita A
Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka 812-82, Japan.
Am J Physiol. 1998 Jul;275(1):H31-40. doi: 10.1152/ajpheart.1998.275.1.H31.
Sarcoplasmic reticulum (SR) Ca2+-ATPase gene expression is reduced in the failing myocardium. However, the functional relevance of these changes to myocardial contractility is not yet established. We assessed myocardial contractile function by analyzing sarcomere motion of isolated myocytes and also quantified SR Ca2+ regulatory protein gene expression by Northern blot analysis in the same hearts obtained from 10 dogs with pacing-induced heart failure (HF; 240 beats/min, 4 wk) and 7 control dogs. Sarcomere-shortening velocity was depressed in HF myocytes, accompanied by the prolongation of intracellular Ca2+ concentration ([Ca2+]i) transient measured by indo 1 fluorescence ratio. SR Ca2+-ATPase mRNA levels (normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA) were significantly depressed in HF, and calsequestrin mRNA was increased. For control and HF dogs, sarcomere-shortening velocity correlated positively with Ca2+-ATPase mRNA levels (r = 0.73, n = 17, P < 0.01) but not with calsequestrin mRNA. Ca2+-ATPase mRNA levels were correlated with 45Ca2+ uptake rate by SR, which was also reduced in HF. Moreover, the inhibition of SR Ca2+-ATPase with thapsigargin or cyclopiazonic acid reproduced in normal myocytes the abnormalities observed in HF myocytes, such as depressed contractility and the prolonged [Ca2+]i transient duration. A downregulation of Ca2+-ATPase gene expression and a resultant decrease in Ca2+ uptake by SR may be responsible for the contractile dysfunction and the alterations of [Ca2+]i transient in HF.
在衰竭心肌中，肌浆网（SR）Ca2+ -ATP酶基因表达降低。然而，这些变化与心肌收缩性的功能相关性尚未明确。我们通过分析分离心肌细胞的肌节运动来评估心肌收缩功能，并通过Northern印迹分析对取自10只因起搏诱导心力衰竭（HF；240次/分钟，4周）的犬和7只对照犬的同一心脏中的SR Ca2+调节蛋白基因表达进行定量。HF心肌细胞的肌节缩短速度降低，同时通过indo 1荧光比率测量的细胞内Ca2+浓度（[Ca2+]i）瞬变延长。HF中SR Ca2+ -ATP酶mRNA水平（以甘油醛-3-磷酸脱氢酶mRNA标准化）显著降低，而肌集钙蛋白mRNA增加。对于对照犬和HF犬，肌节缩短速度与Ca2+ -ATP酶mRNA水平呈正相关（r = 0.73，n = 17，P < 0.01），但与肌集钙蛋白mRNA无关。Ca2+ -ATP酶mRNA水平与SR的45Ca2+摄取率相关，HF中该摄取率也降低。此外，用毒胡萝卜素或环匹阿尼酸抑制SR Ca2+ -ATP酶在正常心肌细胞中重现了HF心肌细胞中观察到的异常，如收缩性降低和[Ca2+]i瞬变持续时间延长。Ca2+ -ATP酶基因表达下调以及由此导致的SR对Ca2+摄取减少可能是HF中收缩功能障碍和[Ca2+]i瞬变改变的原因。
