S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction.

Medizinische Universitätsklinik und Poliklinik III, Otto Meyerhof Zentrum, Universität zu Heidelberg, INF 350, 69115 Heidelberg, Germany.
Molecular Therapy (Impact Factor: 6.43). 01/2006; 12(6):1120-9. DOI: 10.1016/j.ymthe.2005.08.002
Source: PubMed

ABSTRACT 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Low levels of the molecular inotrope S100A1 are sufficient to rescue post-ischemic heart failure (HF). As a prerequisite to clinical application and to determine the safety of myocardial S100A1 DNA-based therapy, we investigated the effects of high myocardial S100A1 expression levels on the cardiac contractile function and occurrence of arrhythmia in a preclinical large animal HF model. At 2 weeks after myocardial infarction domestic pigs presented significant left ventricular (LV) contractile dysfunction. Retrograde application of AAV6-S100A1 (1.5 × 10(13) tvp) via the anterior cardiac vein (ACV) resulted in high-level myocardial S100A1 protein peak expression of up to 95-fold above control. At 14 weeks, pigs with high-level myocardial S100A1 protein overexpression did not show abnormalities in the electrocardiogram. Electrophysiological right ventricular stimulation ruled out an increased susceptibility to monomorphic ventricular arrhythmia. High-level S100A1 protein overexpression in the LV myocardium resulted in a significant increase in LV ejection fraction (LVEF), albeit to a lesser extent than previously reported with low S100A1 protein overexpression. Cardiac remodeling was, however, equally reversed. High myocardial S100A1 protein overexpression neither increases the occurrence of cardiac arrhythmia nor causes detrimental effects on myocardial contractile function in vivo. In contrast, this study demonstrates a broad therapeutic range of S100A1 gene therapy in post-ischemic HF using a preclinical large animal model.Gene Therapy advance online publication, 5 December 2013; doi:10.1038/gt.2013.63.
    Gene therapy 12/2013; · 4.75 Impact Factor
  • Academic Journal of Second Military Medical University 09/2008; 28(3):331-333.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Ca(2+) plays a crucial role in connecting membrane excitability with contraction in myocardium. The hallmark features of heart failure are mechanical dysfunction and arrhythmias; defective intracellular Ca(2+) homeostasis is a central cause of contractile dysfunction and arrhythmias in failing myocardium. Defective Ca(2+) homeostasis in heart failure can result from pathological alteration in the expression and activity of an increasingly understood collection of Ca(2+) homeostatic and structural proteins, ion channels, and enzymes. This review focuses on the molecular mechanisms of defective Ca(2+) cycling in heart failure and considers how fundamental understanding of these pathways may translate into novel and innovative therapies.
    Circulation Research 08/2013; 113(6):690-708. · 11.09 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014