title: Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo.
abstract: BACKGROUND
  The serine-threonine kinase Akt is activated by several ligand-receptor systems previously shown to be cardioprotective. Akt activation reduces cardiomyocyte apoptosis in models of transient ischemia. Its role in cardiac dysfunction or infarction, however, remains unclear.
  
  
  RESULTS
  We examined the effects of a constitutively active Akt mutant (myr-Akt) in a rat model of cardiac ischemia-reperfusion injury. In vivo gene transfer of myr-Akt reduced infarct size by 64% and the number of apoptotic cells by 84% (P<0.005 for each). Ischemia-reperfusion injury decreased regional cardiac wall thickening as well as the maximal rate of left ventricular pressure rise and fall (+dP/dt and -dP/dt). Akt activation restored regional wall thickening and +dP/dt and -dP/dt to levels seen in sham-operated rats. To better understand this benefit, we examined the effects of myr-Akt on hypoxic cardiomyocyte dysfunction in vitro. myr-Akt prevented hypoxia-induced abnormalities in cardiomyocyte calcium transients and shortening. Akt activation also enhanced sarcolemmal expression of Glut-4 in vivo and increased glucose uptake in vitro to the level seen with insulin treatment.
  
  
  CONCLUSIONS
  Akt activation exerts a powerful cardioprotective effect after transient ischemia that probably reflects its ability to both inhibit cardiomyocyte death and improve function of surviving cardiomyocytes. Akt may represent an important nodal target for therapy in ischemic and other heart disease.
authors.affiliation: Program in Cardiovascular Gene Therapy, CVRC, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.forename: J
authors.initials: J
authors.lastname: Tao
authors.forename: F
authors.initials: F
authors.lastname: del Monte
authors.forename: K H
authors.initials: KH
authors.lastname: Lee
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Picard
authors.forename: T L
authors.initials: TL
authors.lastname: Force
authors.forename: T F
authors.initials: TF
authors.lastname: Franke
authors.forename: R J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: A
authors.initials: A
authors.lastname: Rosenzweig
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003331:Coronary Vessels; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D004789:Enzyme Activation / Q000235:genetics; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000235:genetics; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D011518:Proto-Oncogene Proteins; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt