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S100A1 genetically targeted therapy reverses dysfunction of human failing cardiomyocytes
Henriette Brinks1, David Rohde, Mirko Voelkers
1Department of Cardiac and Vascular Surgery, University Hospital Berne, Bern, Switzerland.
Insights
Gene therapy restoring S100A1 protein levels improved key features of human heart failure in cardiomyocytes. This molecular repair offers a promising new therapeutic strategy for heart failure (HF).
Area of Science:
- Cardiology
- Molecular Biology
- Gene Therapy
Background:
- S100A1 protein depletion contributes to heart failure (HF) progression in animal models.
- Cardiac-specific S100A1 gene therapy has shown promise in experimental settings.
- The effect of S100A1 gene therapy on human failing myocardium remains to be elucidated.
Purpose of the Study:
- To investigate if S100A1 gene therapy can ameliorate pathological hallmarks in human failing ventricular cardiomyocytes (HFCMs).
- To assess the impact of S100A1 restoration on cardiac function, calcium handling, and energy metabolism in HFCMs.
Main Methods:
- Human HFCMs were subjected to adenoviral gene transfer with either S100A1 or control cDNA.
- Contractile performance was analyzed using video-edge-detection.
- Calcium handling, signaling pathways, and mitochondrial function were assessed using epifluorescent microscopy and biochemical assays.
Main Results:
- S100A1 gene transfer normalized S100A1 levels and reversed contractile dysfunction in HFCMs.
- Therapy improved calcium handling, reducing diastolic calcium overload and arrhythmogenic calcium leak.
- Mitochondrial function and cellular energy balance (phosphocreatine/adenosine-triphosphate ratio) were restored.
Conclusions:
- Genetic restoration of S100A1 protein levels effectively reverses key pathophysiological features in human failing cardiomyocytes.
- These findings provide the first evidence of S100A1's therapeutic efficacy in human HFCMs.
- This study supports S100A1 gene therapy as a potential molecular-guided treatment for human heart failure.
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 (β-AR) stimulation independent of cAMP-dependent (PKA) and calmodulin-dependent (CaMKII) kinase activity. S100A1 reversed underlying Ca²⁺ handling abnormalities basally and under β-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/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.
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