What question did this study set out to answer?

To determine the electrophysiological and cellular mechanisms through which phosphoinositide-3-kinase-gamma (PI3Kγ) deficiency enhances cardiac contractile function.

April 29, 2005Circulation ResearchOpen Access

Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3Kγ-Deficient Mice

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Population

PI3Kgamma-deficient (PI3Kgamma-/-) mice and isolated cardiomyocytes

Comparison

PI3Kgamma deficiency and pharmacological… vs Control mice and their cardiomyocytes

Design

Preclinical

Authors

BKBenoît‐Gilles KerfantMaastricht University DGDominica GidrewiczUniversity of Calgary HSHui SunWuxi No.2 People's Hospital

Discussion

Member takes

Implication

Animal data suggest PI3Kgamma modulates contractility via cAMP; leaves open human therapeutic relevance.

Key Points

To determine the electrophysiological and cellular mechanisms through which phosphoinositide-3-kinase-gamma (PI3Kγ) deficiency enhances cardiac contractile function.
Isolated cardiomyocytes from PI3Kγ-knockout (PI3Kγ-/-) and control (PI3Kγ+/+ or PI3Kγ+/-) mice and analyzed them under field-stimulation and voltage-clamp configurations.
Assessed L-type Ca2+ currents, K+ currents, action potential duration, excitation-contraction coupling gain, and sarcoplasmic reticulum Ca2+ loading and release fluxes.
Evaluated the regulatory role of cAMP signaling using the cAMP inhibitor Rp-cAMP and the beta-adrenergic agonist isoproterenol.
PI3Kγ-/- cardiomyocytes displayed elevated Ca2+ transient amplitudes, accelerated decay kinetics, increased excitation-contraction coupling gain, and elevated sarcoplasmic reticulum Ca2+ load and release fluxes compared to controls.
L-type Ca2+ currents, K+ currents, and action potential durations did not differ between groups under high Ca2+ buffering, though PI3Kγ-/- cells exhibited an abbreviated Ca2+-dependent inactivation phase and prolonged repolarization under physiological transients.
Pretreatment with Rp-cAMP completely abolished the enhanced excitation-contraction coupling and sarcoplasmic reticulum Ca2+ load in PI3Kγ-/- cells, while isoproterenol increased L-type Ca2+ currents and Ca2+ transients by approximately 2-fold in both groups.

Structured PICO

Population

PI3Kgamma-deficient (PI3Kgamma-/-) mice and isolated cardiomyocytes

Intervention

PI3Kgamma deficiency (genetic knockout) and pharmacological interventions (Rp-cAMP, isoproterenol)

Comparator

Control mice (PI3Kgamma+/+ or PI3Kgamma+/-) and their cardiomyocytes

Outcome

Ca2+ transient amplitudes, decay kinetics, L-type Ca2+ currents, action potential duration, and sarcoplasmic reticulum (SR) Ca2+ loadsurrogate

PI3Kgamma reduces cardiac contractility in a compartmentalized manner by inhibiting cAMP-mediated sarcoplasmic reticulum calcium loading.

Cite This Study

Kerfant et al. (2005) studied this question.

synapsesocial.com/papers/6a83f3aeb5a613d8fb3e9d24 https://doi.org/10.1161/01.res.0000168066.06333.df

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Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3Kγ-Deficient Mice

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Cardiac Sarcoplasmic Reticulum Calcium Release and Load Are Enhanced by Subcellular cAMP Elevations in PI3Kγ-Deficient Mice

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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