Shen Jian-Bing, Shutt Robin, Agosto Mariela, Pappano Achilles, Liang Bruce T
Pat and Jim Calhoun Cardiovascular Center, University of Connecticut School of Medicine, Farmington, Connecticut, USA.
Am J Physiol Heart Circ Physiol. 2009 Apr;296(4):H1089-95. doi: 10.1152/ajpheart.01316.2008. Epub 2009 Feb 6.
Binary cardiac transgenic (Tg) overexpression of P2X(4) receptors (P2X(4)R) improved the survival of the cardiomyopathic calsequestrin (CSQ) mice. Here we studied the mechanism of rescue using binary P2X(4)R/CSQ Tg and CSQ Tg mice as models. Cellular and intact heart properties were determined by simultaneous sarcomere shortening (SS) and Ca(2+) transients in vitro and echocardiography in vivo. Similar to a delay in death, binary mice exhibited a slowed heart failure progression with a greater left ventricular (LV) fractional shortening (FS) and thickness and a concomitant lesser degree of LV dilatation in both systole and diastole at 8 or 12 wk. By 16 wk, binary hearts showed similarly depressed FS and thinned out LV and equal enlargement of LV as did 12-wk-old CSQ hearts. Binary cardiac myocytes showed higher peak basal cell shortening (CS) and SS as well as greater basal rates of shortening and relaxation than did the CSQ myocytes at either 8 or 12 wk. Similar data were obtained in comparing the Ca(2+) transient. At 16 wk, binary myocytes were like the 12-wk-old CSQ myocytes with equally depressed CS, SS, and Ca(2+) transient. CSQ myocytes were longer than myocytes from wild-type and binary mice at 12 wk of age. At 16 wk, the binary myocyte length increased to that of the 12-wk-old CSQ myocyte, parallel to LV dilatation. The data suggest a unique mechanism, which involves a reversal of cardiac myocyte dysfunction and a delay in heart failure progression. It represents an example of targeting the abnormal failing myocyte in treating heart failure.
P2X(4)受体（P2X(4)R）的二元心脏转基因（Tg）过表达改善了心肌钙结合蛋白（CSQ）心肌病小鼠的存活率。在此，我们以二元P2X(4)R/CSQ转基因小鼠和CSQ转基因小鼠为模型研究了拯救机制。通过体外同时进行肌节缩短（SS）和Ca(2+)瞬变以及体内超声心动图来确定细胞和完整心脏的特性。与死亡延迟相似，二元小鼠心力衰竭进展减缓，在8周或12周时左心室（LV）缩短分数（FS）和厚度更大，同时收缩期和舒张期LV扩张程度较小。到16周时，二元心脏的FS同样降低，LV变薄，LV扩大程度与12周龄的CSQ心脏相同。二元心肌细胞在8周或12周时比CSQ心肌细胞表现出更高的基础细胞缩短峰值（CS）和SS，以及更大的基础缩短和舒张速率。在比较Ca(2+)瞬变时获得了类似的数据。在16周时，二元心肌细胞与12周龄的CSQ心肌细胞相似，CS、SS和Ca(2+)瞬变同样降低。12周龄时，CSQ心肌细胞比野生型和二元小鼠的心肌细胞更长。在16周时，二元心肌细胞长度增加到12周龄CSQ心肌细胞的长度，与LV扩张平行。数据表明存在一种独特的机制，该机制涉及心肌细胞功能障碍的逆转和心力衰竭进展的延迟。它代表了在治疗心力衰竭时针对异常衰竭心肌细胞的一个例子。
