The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice.
Members of the mitogen-activated protein kinase (MAPK) cascade such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 are implicated as important regulators of cardiomyocyte hypertrophic growth in culture. However, the role that individual MAPK pathways play in vivo has not been extensively evaluated. Here we generated nine transgenic mouse lines with cardiac-restricted expression of an activated MEK1 cDNA in the heart. MEK1 transgenic mice demonstrated concentric hypertrophy without signs of cardiomyopathy or lethality up to 12 months of age. MEK1 transgenic mice showed a dramatic increase in cardiac function, as measured by echocardiography and isolated working heart preparation, without signs of decompensation over time. MEK1 transgenic mice and MEK1 adenovirus-infected neonatal cardiomyocytes each demonstrated ERK1/2, but not p38 or JNK, activation. MEK1 transgenic mice and MEK1 adenovirus-infected cultured cardiomyocytes were also partially resistant to apoptotic stimuli. The results of the present study indicate that the MEK1-ERK1/2 signaling pathway stimulates a physiologic hypertrophy response associated with augmented cardiac function and partial resistance to apoptotsis.
Pubmed ID: 11101507 RIS Download
Actinin | Adenoviridae | Age Factors | Animals | Animals, Newborn | Apoptosis | Body Weight | Cardiomegaly | Caspase 3 | Caspases | Cells, Cultured | DNA Fragmentation | DNA, Complementary | Echocardiography | Electrophoresis, Polyacrylamide Gel | Immunohistochemistry | In Situ Nick-End Labeling | Leucine | MAP Kinase Kinase 1 | MAP Kinase Signaling System | Mice | Mice, Transgenic | Mitogen-Activated Protein Kinase 1 | Mitogen-Activated Protein Kinase 3 | Mitogen-Activated Protein Kinase 8 | Mitogen-Activated Protein Kinase Kinases | Mitogen-Activated Protein Kinases | Myocardium | Organ Size | Plasmids | Protein-Serine-Threonine Kinases | RNA | Rats | Reperfusion Injury | Reverse Transcriptase Polymerase Chain Reaction | Signal Transduction