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Heart failure-inducible gene therapy targeting protein phosphatase 1 prevents progressive left ventricular remodeling
Yosuke Miyazaki1, Yasuhiro Ikeda, Kozo Shiraishi
1Department of Medicine and Clinical Science, Division of Cardiology, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Background:
The targeting of Ca(2+) cycling has emerged as a potential therapy for the treatment of severe heart failure. These approaches include gene therapy directed at overexpressing sarcoplasmic reticulum (SR) Ca(2+) ATPase, or ablation of phospholamban (PLN) and associated protein phosphatase 1 (PP1) protein complexes. We previously reported that PP1β, one of the PP1 catalytic subunits, predominantly suppresses Ca(2+) uptake in the SR among the three PP1 isoforms, thereby contributing to Ca(2+) downregulation in failing hearts. In the present study, we investigated whether heart-failure-inducible PP1β-inhibition by adeno-associated viral-9 (AAV9) vector mediated gene therapy is beneficial for preventing disease progression in genetic cardiomyopathic mice.
Methods:
We created an adeno-associated virus 9 (AAV9) vector encoding PP1β short-hairpin RNA (shRNA) or negative control (NC) shRNA. A heart failure inducible gene expression system was employed using the B-type natriuretic protein (BNP) promoter conjugated to emerald-green fluorescence protein (EmGFP) and the shRNA sequence. AAV9 vectors (AAV9-BNP-EmGFP-PP1βshRNA and AAV9-BNP-EmGFP-NCshRNA) were injected into the tail vein (2×10(11) GC/mouse) of muscle LIM protein deficient mice (MLPKO), followed by serial analysis of echocardiography, hemodynamic measurement, biochemical and histological analysis at 3 months.
Results:
In the MLPKO mice, BNP promoter activity was shown to be increased by detecting both EmGFP expression and the induced reduction of PP1β by 25% in the myocardium. Inducible PP1βshRNA delivery preferentially ameliorated left ventricular diastolic function and mitigated adverse ventricular remodeling. PLN phosphorylation was significantly augmented in the AAV9-BNP-EmGFP-PP1βshRNA injected hearts compared with the AAV9-BNP-EmGFP-NCshRNA group. Furthermore, BNP production was reduced, and cardiac interstitial fibrosis was abrogated at 3 months.
Conclusion:
Heart failure-inducible molecular targeting of PP1β has potential as a novel therapeutic strategy for heart failure.
Insights
Gene therapy targeting protein phosphatase 1 beta (PP1β) improved heart function in mice with heart failure. This approach inhibited PP1β in failing hearts, offering a potential new treatment for heart failure.
Area of Science:
- Cardiology
- Molecular Biology
- Gene Therapy
Background:
- Calcium (Ca2+) cycling is a key target for heart failure therapy.
- Protein phosphatase 1 beta (PP1β) suppresses sarcoplasmic reticulum Ca2+ uptake, contributing to heart failure.
- Investigating PP1β inhibition as a therapeutic strategy for heart failure is crucial.
Purpose of the Study:
- To investigate the efficacy of heart failure-inducible PP1β inhibition using adeno-associated virus 9 (AAV9) gene therapy.
- To assess the therapeutic benefits of this approach in preventing disease progression in genetic cardiomyopathic mice.
Main Methods:
- Created AAV9 vectors encoding PP1β short-hairpin RNA (shRNA) or negative control (NC) shRNA.
- Utilized a heart failure-inducible gene expression system (BNP promoter-EmGFP-shRNA).
- Injected AAV9 vectors into muscle LIM protein deficient (MLPKO) mice, followed by comprehensive analysis.
Main Results:
- PP1β was reduced by 25% in MLPKO mouse myocardium, with increased BNP promoter activity.
- PP1β inhibition improved left ventricular diastolic function and reduced adverse ventricular remodeling.
- PLN phosphorylation increased, BNP production decreased, and cardiac fibrosis was abrogated.
Conclusions:
- Heart failure-inducible molecular targeting of PP1β shows promise as a novel therapeutic strategy.
- This gene therapy approach effectively ameliorated heart failure pathology in a mouse model.
- Targeting PP1β represents a potential new avenue for treating heart failure.
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