The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophyin transgenic mice

Members of the mitogen-activated protein kinase (MAPK) cascade such as extr acellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 are implicated as important regulators of cardiomyocyte hypertrophic gr owth in culture. However, the role that individual MAPK pathways play in vi vo has not been extensively evaluated. Here we generated nine transgenic mo use lines with cardiac-restricted expression of an activated MEK1 cDNA in t he heart. MEK1 transgenic mice demonstrated concentric hypertrophy without signs of cardiomyopathy or lethality up to 12 months of age. MEK1 transgeni c mice showed a dramatic increase in cardiac function, as measured by echoc ardiography and isolated working heart preparation, without signs of decomp ensation over time. MEK1 transgenic mice and MEK1 adenovirus-infected neona tal 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 pre sent study indicate that the MEK1-ERK1/2 signaling pathway stimulates a phy siologic hypertrophy response associated with augmented cardiac function an d partial resistance to apoptotsis.