S100A1 Gene Therapy Preserves in Vivo Cardiac Function after Myocardial Infarction

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany
Molecular Therapy (Impact Factor: 6.23). 01/2006; 12(6):1120-9. DOI: 10.1016/j.ymthe.2005.08.002
Source: PubMed


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 decompensation 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/AdS100A1), 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 Ca(2+) 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.

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Available from: Oliver J Müller
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    • "Taken together, these data provide evidence that S100A1 represents an essential prerequisite for cardiac adaption to chronic hemodynamic stress and ischemic damage. Considering the hypercontractile phenotype of S100A1-overexpressing cardiomyocytes, different in vivo strategies, including transgenic mice and S100A1 gene delivery, have been used to support this concept [27, 48, 62, 71]. Compared with WT controls, transgenic mice with a cardiac-restricted overexpression of S100A1 (STG) presented a markedly augmented cardiac function that remained elevated in response to βAR stimulation [48, 62]. "
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    • "In line with cardiac specific overexpression of S100A1 in transgenic mice, viral-based overexpression of S100A1 in rabbit and rat hearts and isolated cardiomyocytes recapitulated the hypercontractile phenotype based on enhanced Ca2+ cycling but independent, and additive to beta-AR signalling [15, 17, 18, 33, 34]. Therefore, it is interesting to note that acute or chronic elevated S100A1 proteins in cardiomyocytes induce sustained cardiac inotropy, without toxic effects to the cardiomyocytes. "
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