Enhancing repair of the mammalian heart.
The injured mammalian heart is particularly susceptible to tissue deterioration, scarring, and loss of contractile function in response to trauma or sustained disease. We tested the ability of a locally acting insulin-like growth factor-1 isoform (mIGF-1) to recover heart functionality, expressing the transgene in the mouse myocardium to exclude endocrine effects on other tissues. supplemental mIGF-1 expression did not perturb normal cardiac growth and physiology. Restoration of cardiac function in post-infarct mIGF-1 transgenic mice was facilitated by modulation of the inflammatory response and increased antiapoptotic signaling. mIGF-1 ventricular tissue exhibited increased proliferative activity several weeks after injury. The canonical signaling pathway involving Akt, mTOR, and p70S6 kinase was not induced in mIGF-1 hearts, which instead activated alternate PDK1 and SGK1 signaling intermediates. The robust response achieved with the mIGF-1 isoform provides a mechanistic basis for clinically feasible therapeutic strategies for improving the outcome of heart disease.
Santini
Maria Paola
MP
European Molecular Biology Laboratory, Mouse Biology Unit Monterotondo, Rome, Italy.
Tsao
Lana
L
Monassier
Laurent
L
Theodoropoulos
Catherine
C
Carter
Janice
J
Lara-Pezzi
Enrique
E
Slonimsky
Esfir
E
Salimova
Ekaterina
E
Delafontaine
Patrice
P
Song
Yao-Hua
YH
Bergmann
Martin
M
Freund
Christian
C
Suzuki
Ken
K
Rosenthal
Nadia
N
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002921:Cicatrix / Q000503:physiopathology / Q000517:prevention & control; D018076:DNA, Complementary / Q000235:genetics; D005786:Gene Expression Regulation; D007249:Inflammation; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D020127:Recovery of Function; D015398:Signal Transduction / Q000502:physiology; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
D018076:DNA, Complementary; D020033:Protein Isoforms; D007334:Insulin-Like Growth Factor I