Elevated myocardial Akt signaling ameliorates doxorubicin-induced congestive heart failure and promotes heart growth.
Doxorubicin is a chemotherapeutic agent that can induce cardiotoxicity and congestive heart failure (CHF). In this study we tested whether intracoronary Akt1 gene delivery could inhibit doxorubicin-induced CHF. Saline or a replication defective adenoviral vector expressing constitutively-active Akt1 (myrAkt) or beta-galactosidase (betagal) was delivered to the myocardium of 8 week old rats one day prior to initiating doxorubicin administration. In animals receiving saline or betagal, doxorubicin resulted in significant decreases in cardiac function and retarded post-natal heart growth at the 5 weeks time point. In contrast, transduction of myrAkt protected hearts against doxorubicin-induced decreases in fractional shortening and cardiac index, and improved left ventricular function at 5 weeks time point. Delivery of myrAkt also reversed the doxorubicin-induced reduction in post-natal heart growth and diminished lung edema. These data show that myocardial Akt can inhibit doxorubicin-induced reductions in cardiac function and growth, suggesting that manipulation of this signaling pathway may have utility for the treatment of congestive heart failure.
Taniyama
Yoshiaki
Y
Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
Walsh
Kenneth
K
D000818:Animals; D001794:Blood Pressure; D004317:Doxorubicin / Q000494:pharmacology*; D004452:Echocardiography; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006321:Heart / Q000254:growth & development*; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics* / Q000628:therapy*; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D011518:Proto-Oncogene Proteins; D004317:Doxorubicin; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt