ArticleThe Journal of clinical investigation2010
Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging.
Article in The Journal of clinical investigation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 99 citations in OpenAlex.
- Genomic Evidence for Natural Selection Underlying High-Altitude Adaptive Hemoglobin Levels Among Peruvian Andeans.Genome biology and evolution · 2026Article
- Cardiac gene therapy makes a comeback.Nature medicine · 2025Article
- Cardioprotective effects of semaglutide on isolated human ventricular myocardium.European journal of heart failure · 2025Article
- Integrative human atrial modelling unravels interactive protein kinase A and Ca2+/calmodulin-dependent protein kinase II signalling as key determinants of atrial arrhythmogenesis.Cardiovascular research · 2023Article
- Emerging Antiarrhythmic Drugs for Atrial Fibrillation.International journal of molecular sciences · 2022Review
- Serine-threonine protein phosphatase regulation of Cx43 dephosphorylation in arrhythmogenic disorders.Cellular signalling · 2021Review
- Molecular noise filtering in the β-adrenergic signaling network by phospholamban pentamers.Cell reports · 2021Article
- Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control.Cardiovascular research · 2021Article
- Current Landscape of Heart Failure Gene Therapy.Journal of the American Heart Association · 2019Review
- Functions and therapeutic potential of protein phosphatase 1: Insights from mouse genetics.Biochimica et biophysica acta. Molecular cell research · 2019Review
- Age-Dependent Protein Expression of Serine/Threonine Phosphatases and Their Inhibitors in the Human Cardiac Atrium.Advances in medicine · 2019Article
- Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression.Circulation · 2018Article
- AAV-9 mediated phosphatase-1 inhibitor-1 overexpression improves cardiac contractility in unchallenged mice but is deleterious in pressure-overload.Gene therapy · 2018Article
- Redox regulation of the actin cytoskeleton and its role in the vascular system.Free radical biology & medicine · 2017Review
- Chronic loss of inhibitor-1 diminishes cardiac RyR2 phosphorylation despite exaggerated CaMKII activity.Naunyn-Schmiedeberg's archives of pharmacology · 2017Article
- Negative Adrenergic Feedback Specific to Phospholamban.JACC. Basic to translational science · 2017Article
- Profiling analysis of long non-coding RNAs in early postnatal mouse hearts.Scientific reports · 2017Article
- The role of Epac in the heart.Cellular and molecular life sciences : CMLS · 2017Review
- Regulating the regulator: Insights into the cardiac protein phosphatase 1 interactome.Journal of molecular and cellular cardiology · 2016Review
- Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias.Journal of molecular and cellular cardiology · 2015Article
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phosphatase inhibitor-1 (I-1) is a distal amplifier element of beta-adrenergic signaling that functions by preventing dephosphorylation of downstream targets. I-1 is downregulated in human failing hearts, while overexpression of a constitutively active mutant form (I-1c) reverses contractile dysfunction in mouse failing hearts, suggesting that I-1c may be a candidate for gene therapy. We generated mice with conditional cardiomyocyte-restricted expression of I-1c (referred to herein as dTGI-1c mice) on an I-1-deficient background. Young adult dTGI-1c mice exhibited enhanced cardiac contractility but exaggerated contractile dysfunction and ventricular dilation upon catecholamine infusion. Telemetric ECG recordings revealed typical catecholamine-induced ventricular tachycardia and sudden death. Doxycycline feeding switched off expression of cardiomyocyte-restricted I-1c and reversed all abnormalities. Hearts from dTGI-1c mice showed hyperphosphorylation of phospholamban and the ryanodine receptor, and this was associated with an increased number of catecholamine-induced Ca2+ sparks in isolated myocytes. Aged dTGI-1c mice spontaneously developed a cardiomyopathic phenotype. These data were confirmed in a second independent transgenic mouse line, expressing a full-length I-1 mutant that could not be phosphorylated and thereby inactivated by PKC-alpha (I-1S67A). In conclusion, conditional expression of I-1c or I-1S67A enhanced steady-state phosphorylation of 2 key Ca2+-regulating sarcoplasmic reticulum enzymes. This was associated with increased contractile function in young animals but also with arrhythmias and cardiomyopathy after adrenergic stress and with aging. These data should be considered in the development of novel therapies for heart failure.
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