Akt and PI 3-kinase signaling in cardiomyocyte hypertrophy and survival.
In many systems, activation of the "protein and lipid kinase" phosphoinositide 3-kinase (PI 3-kinase) and its downstream serine-threonine kinase effector, Akt (or Protein Kinase B), provide a potent stimulus for cell proliferation, growth, and survival. In the heart, constrained by the limited proliferative capacity of cardiomyocytes, this pathway plays a key role in regulating cardiomyocyte growth and survival, with little effect on proliferation. Simultaneously, PI 3-kinase and Akt are important modulators of metabolic substrate utilization and cardiomyocyte function. Thus, the convergent signaling pathways controlling so many clinically important phenotypes of the cardiomyocyte suggest it holds promise as a therapeutic target in a variety of cardiac diseases. However, the similar role of PI 3-kinase/Akt signaling in neoplasia suggests the difficulty of activating this pathway in the heart without invoking adverse consequences elsewhere. Here we review evidence regarding the role of PI 3-kinase/Akt in controlling cardiomyocyte growth and survival, and discuss the implications for therapeutic strategies.
Matsui
Takashi
T
Program in Cardiovascular Gene Therapy, CVRC and Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Room 2600, Boston, MA 02129, USA.
Nagoshi
Tomohisa
T
Rosenzweig
Anthony
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D009202:Cardiomyopathies / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006801:Humans; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human