| First Author | Zhabyeyev P | Year | 2014 |
| Journal | J Mol Cell Cardiol | Volume | 77 |
| Pages | 155-9 | PubMed ID | 25451171 |
| Mgi Jnum | J:225771 | Mgi Id | MGI:5694325 |
| Doi | 10.1016/j.yjmcc.2014.10.008 | Citation | Zhabyeyev P, et al. (2014) Dual loss of PI3Kalpha and PI3Kgamma signaling leads to an age-dependent cardiomyopathy. J Mol Cell Cardiol 77:155-9 |
| abstractText | Phosphatidylinositide 3-kinase (PI3K) signaling plays a critical role in maintaining normal cardiac structure and function. PI3Kalpha and PI3Kgamma 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 p110gamma(-/-) (PI3KgammaKO) with cardiac-specific PI3KalphaDN 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, PI3KalphaDN, and PI3KgammaKO 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 PI3Kalpha and PI3Kgamma isoforms results in an age-dependent cardiomyopathy implying that long-term exposure to pan-PI3K inhibitors may lead to severe cardiotoxicity. |
