Abstract 13474: PI3Kα is Required for Recovery from Transient Cre/tamoxifen Induced Cardiotoxicity
Introduction: Tamoxifen activation of the Cre recombinase transgene is a commonly used model for tissue and time-specific gene deletion. Tamoxifen treatment combined with Cre causes a transient cardiomyopathy. The phosphatidylinositol 3-kinase (PI3K)α signaling pathway has demonstrated a protective role in numerous models for heart disease. We hypothesize that loss of PI3Kα may interfere with the recovery from Cre/tamoxifen induced cardiotoxicity.
Methods: Mice expressing Cre under the control of the αMHC promoter and loxP sites inserted adjacent to the PI3Kα gene (PIK3CA) were treated with tamoxifen by oral gavage for 4 days at either 40 mg/kg/day (low dose) (n=5) or 60 mg/kg/day (high dose)(n=10-14). A control Cre transgenic cohort and Cre with PI3Kβ gene (PIK3CB) loxP sites were also treated with tamoxifen. Cardiac function was assessed using echocardiography at days 10 and 28 from start of tamoxifen.
Results: All cohorts with high dose tamoxifen showed significantly reduced systolic function at day 10 (ejection fraction (EF): 34.3±4.6, 41.4±1.3 and 42.1±6.3% for PI3Kα/loxP, PI3Kβ/LoxP and controls respectively), with increased mortality (30%) in PI3Kβ/LoxP mice compared to (10%) PI3Kα/loxP and (0%) control mice. Control mice and PI3Kβ/LoxP conditional knockouts showed recovery of systolic function to normal levels by day 28 (EF: 57.4±0.5% and 54.6±2.2 respectively), but PI3Kα hearts had continued systolic dysfunction at day 28 (EF: 35.4±4.8%) with increased LV end diastolic dimension (LVEDD): 4.51±0.18 mm vs 3.90±0.05 mm for control mice. All cohorts treated with low dose tamoxifen showed normal echocardiographic results at day 10 (EF: 64.2±1.1%), and Western blot analysis confirmed a 82.3±3.2% reduction in PI3Kα protein levels in PI3Kα knockout ventricle tissue compared to control hearts.
Conclusions: We conclude that PI3Kα can be deleted in adult mice hearts without causing a severe cardiac phenotype. However, PI3Kα is required for recovery from Cre/tamoxifen induced cardiotoxicity at high tamoxifen doses. Loss of PI3Kα plays a critical role in the recovery from tamoxifen-induced cardiomyopathy, an important technical consideration for anyone using this system to knock out a gene that may hamper recovery from Cre/tamoxifen toxicity.
- © 2012 by American Heart Association, Inc.