S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes
| Autor: | Carolin Lerchenmüller, Gang Qiu, Patrick Most, Arjang Ruhparwar, David Rohde, Mirko Voelkers, Nicole Herzog, Hugo A. Katus, Sven T. Pleger, Henriette Brinks, Thierry Carrel, Joseph E. Rabinowitz, Andrea D. Eckhart, Paul J. Mather, Walter J. Koch, Scott C. Silvestry |
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| Rok vydání: | 2010 |
| Předmět: |
medicine.medical_specialty
medicine.medical_treatment Stimulation 030204 cardiovascular system & hematology Pharmacology Ryanodine receptor 2 Phosphocreatine Targeted therapy 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Ca2+/calmodulin-dependent protein kinase Internal medicine S100A1 medicine Myocyte Humans Myocytes Cardiac Kinase activity Cells Cultured 030304 developmental biology Heart Failure 0303 health sciences business.industry S100 Proteins Genetic Therapy medicine.disease gene therapy 3. Good health sarcoplasmic reticulum Endocrinology chemistry Heart failure Calcium business Cardiology and Cardiovascular Medicine |
| Zdroj: | Journal of the American College of Cardiology. 58(9) |
| ISSN: | 1558-3597 |
| Popis: | Objectives This study investigated the hypothesis whether S100A1 gene therapy can improve pathological key features in human failing ventricular cardiomyocytes (HFCMs). Background Depletion of the Ca 2+ -sensor protein S100A1 drives deterioration of cardiac performance toward heart failure (HF) in experimental animal models. Targeted repair of this molecular defect by cardiac-specific S100A1 gene therapy rescued cardiac performance, raising the immanent question of its effects in human failing myocardium. Methods Enzymatically isolated HFCMs from hearts with severe systolic HF were subjected to S100A1 and control adenoviral gene transfer and contractile performance, calcium handling, signaling, and energy homeostasis were analyzed by video-edge-detection, FURA2-based epifluorescent microscopy, phosphorylation site-specific antibodies, and mitochondrial assays, respectively. Results Genetically targeted therapy employing the human S100A1 cDNA normalized decreased S100A1 protein levels in HFCMs, reversed both contractile dysfunction and negative force-frequency relationship, and improved contractile reserve under beta-adrenergic receptor (β-AR) stimulation independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 reversed underlying Ca 2+ handling abnormalities basally and under β-AR stimulation shown by improved SR Ca 2+ handling, intracellular Ca 2+ transients, diastolic Ca 2+ overload, and diminished susceptibility to arrhythmogenic SR Ca 2+ leak, respectively. Moreover, S100A1 ameliorated compromised mitochondrial function and restored the phosphocreatine/adenosine-triphosphate ratio. Conclusions Our results demonstrate for the first time the therapeutic efficacy of genetically reconstituted S100A1 protein levels in HFCMs by reversing pathophysiological features that characterize human failing myocardium. Our findings close a gap in our understanding of S100A1's effects in human cardiomyocytes and strengthen the rationale for future molecular-guided therapy of human HF. |
| Databáze: | OpenAIRE |
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