S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction
S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction
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DOI：
10.1016/j.ymthe.2005.08.002
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发表时间：
2005-12-01
影响因子：
12.4
通讯作者：
Most, P
中科院分区：
文献类型：
--
作者：
Pleger, ST;Remppis, A;Most, P
心肌梗死（MI）代表了一个巨大的临床挑战，因为缺血性损伤导致的心肌损失与左心室（LV）功能受损相关，通常导致急性心脏代偿失调或慢性心力衰竭。S100 A1最近被确定为体外和体内心肌收缩力的正性肌力调节剂。在这里，我们探讨心肌S100 A1基因治疗的策略，无论是在时间，或2小时后，MI，以保护全球心脏功能。大鼠接受低温诱导的MI和体内冠状动脉内递送腺病毒转基因（4 × 10（10）pfu）。动物接受盐水（MI）、S100 A1腺病毒（MI/AdS 100 A1）、对照腺病毒（MI/AdGFP）或假手术。S100 A1基因递送在MI后1周保留了整体体内LV功能。左室功能的保存主要是由于S100 A1介导的剩余的，可行的心肌收缩性的增益，因为收缩参数和Ca 2+，分离的MI/AdS 100 A1心肌细胞的瞬态显着增强相比，从MI/AdGFP和假手术组分离的心肌细胞。此外，S100 A1基因治疗保留了心脏β-肾上腺素能正性肌力储备，这与GRK 2上调的减弱有关。此外，S100 A1过表达减少MI后1周的心脏肥大。总的来说，我们的数据表明，S100 A1基因治疗提供了一种潜在的新的治疗策略，以维持Mi后心脏的收缩性能。
Myocardial infarction (MI) represents an enormous clinical challenge as loss of myocardium due to ischemic injury is associated with compromised left ventricular (LV) function often leading to acute cardiac clecompensation or chronic heart failure. S100A1 was recently identified as a positive inotropic regulator of myocardial contractility in vitro and in vivo. Here, we explore the strategy of myocardial S100A1 gene therapy either at the time of, or 2 h after, MI to preserve global heart function. Rats underwent cryothermia-induced MI and in vivo intracoronary delivery of adenoviral transgenes (4 x 10(10) pfu). Animals received saline (MI), the S100A1 adenovirus (MI/AdS100Al), a control adenovirus (MI/AdGFP), or a sham operation. S100A1 gene delivery preserved global in vivo LV function 1 week after MI. Preservation of LV function was due mainly to S100A1-mediated gain of contractility of the remaining, viable myocardium since contractile parameters and Ca2+, transients of isolated MI/AdS100A1 myocytes were significantly enhanced compared to myocytes isolated from both MI/AdGFP and sham groups. Moreover, S100A1 gene therapy preserved the cardiac beta-adrenergic inotropic reserve, which was associated with the attenuation of GRK2 up-regulation. Also, S100A1 overexpression reduced cardiac hypertrophy 1 week post-Mi. Overall, our data indicate that S100A1 gene therapy provides a potential novel treatment strategy to maintain contractile performance of the post-Mi heart.