Dual loss of PI3K alpha and PI3K gamma signaling leads to an age-dependent cardiomyopathy

作者：Zhabyeyev Pavel; McLean Brent; Patel Vaibhav B; Wang Wang; Ramprasath Tharmarajan; Oudit Gavin Y^*

来源：Journal of Molecular and Cellular Cardiology, 2014, 77: 155-159.

DOI：10.1016/j.yjmcc.2014.10.008

• Signaling
• Cardiomyopathy
• Phosphatidylinositol-4,5-bisphosphate 3-kinase
• Aging

Phosphatidylinositide 3-kinase (PI3K) signaling plays a critical role in maintaining normal cardiac structure and function. PI3K alpha and PI3K gamma are the dominant cardiac isoforms and have both adaptive and maladaptive roles in heart disease. Broad spectrum PI3K inhibitors are emerging as potential new chemotherapeutic agents which may have deleterious long-term effects on the heart. We created a double mutant (PI3KDM) model by crossing p110 gamma(-/-) (PI3K gamma KO) with cardiac-specific PI3K alpha DN mice and studied cardiac structure and function at 1-year of age. Pressure-volume loop analysis and echocardiographic assessment showed PI3KDM mice developed marked impairment in systolic function while the wildtype, PI3K alpha DN, and PI3K gamma KO mice maintained normal systolic and diastolic function at 1-year of age. The PI3KDM hearts displayed increased expression of disease markers, increased myocardial fibrosis and matrix metalloproteinase (MMP) activity, depolymerization of intracellular F-actin, loss of phospho(threonine-308)-Akt, and normalization of phospho-Erk1/2 signaling. Dual loss of PI3K alpha and PI3K gamma isoforms results in an age-dependent cardiomyopathy implying that long-term exposure to pan-PI3K inhibitors may lead to severe cardiotoxicity.

• 出版日期2014-12