Deletion of Akt1 causes heart defects and abnormal cardiomyocyte proliferation.
The PI3K-PDK1-PKB/Akt (PI3K, phosphoinositide-3 kinase; PDK1, phosphoinositide-dependent protein kinase 1; PKB, protein kinase B) signaling pathway plays a critical role in a variety of biological processes including cell survival, growth and proliferation, metabolism and organogenesis. Previously, we generated Akt1-deficient mice and found high neonatal mortality with unknown causes. Here we report that histological analysis of Akt1-deficient embryos and newborns revealed heart defects and decreased cell proliferation. Echocardiographic study of Akt1-deficient mice indicated decreased heart function. Further investigation revealed that Akt1 deficiency caused substantial activation of p38MAPK in the heart. Breeding the Akt1-deficient mice to mice that were heterozygous for a null p38α partially rescued the heart defects, significantly decreased post-natal mortality, and restored normal patterns of cardiomyocyte proliferation. Our study suggests that Akt1 is essential for heart development and function, in part, through suppression of p38MAPK activation.
Chang
Zai
Z
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, Nanjing, China.
Zhang
Qin
Q
Feng
Qiuting
Q
Xu
Jie
J
Teng
Teng
T
Luan
Qing
Q
Shan
Congjia
C
Hu
Yali
Y
Hemmings
Brian A
BA
Gao
Xiang
X
Yang
Zhongzhou
Z
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation; D005260:Female; D006330:Heart Defects, Congenital / Q000000981:diagnostic imaging / Q000196:embryology* / Q000201:enzymology / Q000235:genetics*; D006579:Heterozygote; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology*; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014463:Ultrasonography
D064413:3-Phosphoinositide-Dependent Protein Kinases; C514862:Akt1 protein, mouse; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048308:Mitogen-Activated Protein Kinase 14