Constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice but is deleterious after catecholaminergic stress and with aging
Key result
Conditional expression of constitutively active phosphatase inhibitor-1 enhanced cardiac contractility in young mice but caused arrhythmias and cardiomyopathy after adrenergic stress and with aging.
Why the study?
Does conditional expression of constitutively active phosphatase inhibitor-1 improve cardiac contractility without causing adverse effects under stress or aging in mice?
Population
Young adult and aged mice with conditional cardiomyocyte-restricted expression of a constitutively active…
Comparison
Conditional cardiomyocyte-restricted expression… vs Doxycycline feeding to switch off expression of…
Design
Preclinical
Authors
Discussion
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Implication
Raises arrhythmia and cardiomyopathy risks for I-1c gene therapy; leaves open viability in unstressed models.
Structured PICO
Does conditional expression of constitutively active phosphatase inhibitor-1 improve cardiac contractility without causing adverse effects under stress or aging in mice?
P
Population
Young adult and aged mice with conditional cardiomyocyte-restricted expression of a constitutively active mutant form of phosphatase inhibitor-1 (I-1c) on an I-1-deficient background (dTGI-1c mice), and a second independent transgenic mouse line expressing I-1S67A.
I
Intervention
Conditional cardiomyocyte-restricted expression of constitutively active phosphatase inhibitor-1 (I-1c or I-1S67A).
C
Comparator
Doxycycline feeding to switch off expression of cardiomyocyte-restricted I-1c.
O
Outcome
Cardiac contractility, response to catecholamine infusion (contractile dysfunction, ventricular dilation, arrhythmias, sudden death), and age-related cardiomyopathic changes.surrogate
While constitutively active phosphatase inhibitor-1 improves cardiac contractility in young mice, it leads to deleterious arrhythmias and cardiomyopathy under adrenergic stress and aging, raising safety concerns for its potential use as a heart failure gene therapy.
Cite This Study
Wittköpper et al. (2010) studied Heart failure and cardiomyopathy. Constitutively active phosphatase inhibitor-1 (I-1c or I-1S67A) expression was evaluated on Cardiac contractility, arrhythmias, and cardiomyopathy. Conditional expression of constitutively active phosphatase inhibitor-1 enhanced cardiac contractility in young mice but caused arrhythmias and cardiomyopathy after adrenergic stress and with aging.