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The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice
O F Bueno1, L J De Windt, K M Tymitz
1Department of Pediatrics, University of Cincinnati, Division of Molecular Cardiovascular Biology, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
Abstract:
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.
Insights
Activating the MEK1-ERK1/2 pathway in mice stimulates physiologic cardiac hypertrophy, enhancing heart function and providing resistance to apoptosis. This study clarifies the in vivo role of specific mitogen-activated protein kinase (MAPK) pathways in the heart.
Area of Science:
- Cardiovascular biology
- Molecular signaling
- Physiology
Background:
- Mitogen-activated protein kinase (MAPK) pathways, including ERK, JNK, and p38, are known regulators of cardiomyocyte hypertrophy in vitro.
- The specific roles of individual MAPK pathways in vivo cardiac hypertrophy remain incompletely understood.
Purpose of the Study:
- To investigate the in vivo function of the MEK1-ERK1/2 signaling pathway in cardiac hypertrophy and function.
- To determine the effects of sustained MEK1 activation on cardiac structure, function, and apoptosis resistance.
Main Methods:
- Generation of nine transgenic mouse lines with cardiac-restricted expression of activated MEK1 cDNA.
- Assessment of cardiac hypertrophy, function (echocardiography, working heart preparation), and signaling pathway activation (ERK1/2, p38, JNK).
- Evaluation of resistance to apoptotic stimuli in MEK1 transgenic mice and MEK1-infected cardiomyocytes.
Main Results:
- MEK1 transgenic mice developed concentric cardiac hypertrophy without cardiomyopathy or lethality.
- Significant increases in cardiac function were observed, with no signs of decompensation over time.
- Activation of ERK1/2, but not p38 or JNK, was confirmed in MEK1 transgenic hearts and cardiomyocytes.
- MEK1 activation conferred partial resistance to apoptotic stimuli.
Conclusions:
- The MEK1-ERK1/2 signaling pathway promotes a physiologic cardiac hypertrophy response in vivo.
- This pathway enhances cardiac function and provides a degree of protection against apoptosis.
- Findings highlight the specific role of the MEK1-ERK1/2 axis in adaptive cardiac remodeling.