Role of the Phosphoinositide 3-Kinase Pathway in Cardiac Hypertrophy

Phosphoinositide 3-kinase (PI3K) is a lipid kinase that catalyzes the addition of a phosphate molecule specifically to the 3-position of the inositol ring of phosphoinositides. Biochemical studies using cultured mammalian cells show that PI3K is activated by receptor tyrosine kinases that include insulin or insulin-like growth factors, and PI3K regulates the activities of several downstream molecules such as Akt, p70 ribosomal S6 kinase, and glycogen synthase kinase-3β. The mammalian target of rapamycin, an intracellular target of the immunosuppressant rapamycin, interacts with the PI3K pathway. PI3K regu lates diverse cellular activities, including growth, DNA synthesis, apoptosis, and cytoskeletal organization in cultured cells. Recent genetic studies in Drosophila reveal that the PI3K pathway regulates organ and body size in the developmental process in flies. Various agonists or stimuli activate PI3K or its downstream effectors in cultured myocytes and heart tissue. Perturbation of the PI3K pathway significantly modulates the phenotype of cultured myocytes and the intact heart. Since agonists that activate PI3K, such as growth hormone, have been implicated in the treatment of heart failure, further studies elucidating the role of PI3K and its downstream effectors in the heart may be useful for the development of new strategies to treat cardiac hypertrophy and failure.