Transgenic mice with cardiac-specific over-expression of MLK7 have increased mortality when exposed to chronic beta-adrenergic stimulation.
Mixed lineage kinase 7 (MLK7) is a recently identified mitogen-activated protein kinase kinase kinase with enriched expression in skeletal muscle and heart. When over-expressed in cardiac myocytes, MLK7 activates both the p38 and c-Jun N-terminal kinase (JNK) stress-activated pathways and induces a cellular phenotype characteristic of cardiac hypertrophy, including a fetal gene expression pattern and increased protein synthesis. We sought to determine the effect of MLK7 on cardiac function in vivo by generating transgenic (Tg) mice with cardiac restricted over-expression of the enzyme. The mice were viable and demonstrated no visible signs of distress at rest. Microscopic examination of the hearts showed myocardial fibrosis and hypertrophy. Hemodynamic analysis of the Tg mice revealed impaired systolic function and significant diastolic dysfunction. Furthermore, significant mortality was observed in MLK7 Tg mice following 24-48 h of isoproterenol administration. Isoproterenol activation of JNK and p38, but not extracellular signal-regulated kinase, was significantly greater in the MLK7 Tg mice compared to littermate controls. These data indicate that MLK7 is an important signal transducer in cardiac compensation. Simultaneous activation of JNK and p38 by MLK7 may contribute to cardiac decompensation during the periods of acute cardiac stress.
Christe
Michael
M
Cardiovascular Discovery Research, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Jin
Najia
N
Wang
Xushan
X
Gould
Kenneth E
KE
Iversen
Philip W
PW
Yu
Xiaohong
X
Lorenz
John N
JN
Kadambi
Vivek
V
Zuckerman
Steve H
SH
Bloem
Laura J
LJ
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage*; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D006333:Heart Failure / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D007545:Isoproterenol / Q000008:administration & dosage*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D020930:MAP Kinase Kinase Kinases / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D018482:Muscle, Skeletal; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D007545:Isoproterenol