S100A1 Genetically Targeted Therapy Reverses Dysfunction of Human Failing Cardiomyocytes

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:58

Article

Brinks, Henriette^2,3  Rohde, David⁸  Voelkers, Mirko⁸  Qiu, Gang¹  Pleger, Sven T.⁸  Herzog, Nicole⁸  Rabinowitz, Joseph³  Ruhparwar, Arjang⁷  Silvestry, Scott⁶  Lerchenmueller, Carolin^1,8  Mather, Paul J.⁵  Eckhart, Andrea D.⁴  Katus, Hugo A.⁸  Carrel, Thierry²  Koch, Walter J.³  Most, Patrick^1,8 

[1] Thomas Jefferson Univ, Lab Cardiac Stem Cell & Gene Therapy, Ctr Translat Med, Philadelphia, PA 19107 USA

[2] Univ Hosp Bern, Dept Cardiac & Vasc Surg, CH-3010 Bern, Switzerland

[3] Thomas Jefferson Univ, George Zallie & Family Lab Cardiovasc Gene Therap, Philadelphia, PA 19107 USA

[4] Thomas Jefferson Univ, Eugene Feiner Lab Vasc Biol & Thrombosis, Philadelphia, PA 19107 USA

[5] Thomas Jefferson Univ, Dept Med, Adv Heart Failure & Cardiac Transplant Ctr, Philadelphia, PA 19107 USA

[6] Thomas Jefferson Univ, Div Cardiothorac Surg, Dept Surg, Philadelphia, PA 19107 USA

[7] Heidelberg Univ, Dept Surg, Div Cardiac Surg, D-6900 Heidelberg, Germany

[8] Heidelberg Univ, Dept Cardiol, Inst Mol & Translat Cardiol, D-69120 Heidelberg, Germany

关键词: calcium;    gene therapy;    heart failure;    S100A1;    sarcoplasmic reticulum;   

DOI  :  10.1016/j.jacc.2011.03.054

来源: Elsevier

【 摘 要 】

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 Ca2+-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 (beta-AR) stimulation independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 reversed underlying Ca2+ handling abnormalities basally and under beta-AR stimulation shown by improved SR Ca2+ handling, intracellular Ca2+ transients, diastolic Ca2+ overload, and diminished susceptibility to arrhythmogenic SR Ca2+ leak, respectively. Moreover, S100A1 ameliorated compromised mitochondrial function and restored the phosphocreatine/adenosinetriphosphate 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. (J Am Coll Cardiol 2011; 58: 966-73) (C) 2011 by the American College of Cardiology Foundation

【 授权许可】

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