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Activation of distinct signal transduction pathways in hypertrophied hearts by pressure and volume overload
T Miyamoto1, Y Takeishi, H Takahashi
1First Department of Internal Medicine, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.
Insights
Distinct hemodynamic overload types activate cardiac signaling pathways differently, influencing cardiac hypertrophy. Understanding these distinct signal transduction pathways is key to developing targeted therapies for heart conditions.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Signal Transduction
Background:
- Hemodynamic overload, either pressure or volume, leads to distinct cardiac remodeling.
- Signal transduction pathways are crucial in mediating cellular responses to stress.
Purpose of the Study:
- To investigate if distinct hemodynamic overload types differentially activate specific signal transduction pathways.
- To explore the role of these pathways in pressure and volume overload-induced cardiac hypertrophy.
Main Methods:
- Induction of pressure and volume overload in rabbits via aortic banding and shunt formation, respectively.
- Western blotting was used to assess phosphorylation of key signaling molecules including MAP kinase families, Akt, and STAT3 in the left ventricular myocardium.
Main Results:
- Pressure overload induced concentric hypertrophy with transient activation of ERK1/2, p38 MAP kinase, and STAT3, and biphasic Akt activation.
- Volume overload induced eccentric hypertrophy with sustained Akt activation and delayed, non-Akt-dependent phosphorylation of GSK-3beta and p70(S6K).
- Distinct temporal activation patterns of signaling molecules were observed between pressure and volume overload models.
Conclusions:
- Cardiac hypertrophy resulting from pressure and volume overload exhibits unique signal transduction pathway activation profiles.
- Stimulus-specific signaling heterogeneity likely contributes to the determination of cardiac hypertrophy type.
Objective:
Two types of hemodynamic overload, pressure and volume overload, result in morphologically distinct types of cardiac remodeling. We explored the possibility that distinct hemodynamic overload may differentially activate the signal transduction pathway.
Methods:
Pressure and volume overload were induced by thoracic aortic banding and carotid-jugular shunt formation in rabbits, respectively. Phosphorylation activities of mitogen-activated protein (MAP) kinase families, Akt, and signal transducer and activator of transcription (STAT) 3 in the left ventricular myocardium were determined by Western blotting using phospho-specific antibodies and were compared between hypertrophied hearts by pressure and volume overload.
Results:
Pressure and volume overload produced concentric and eccentric cardiac hypertrophy in rabbits, respectively. In pressure-overloaded hearts, extracellular signal-regulated kinase (ERK) 1/2, p38 MAP kinase, and STAT3 were transiently activated prior to hypertrophic changes. In contrast, activation of ERK1/2, but not p38 MAP kinase and STAT3, was observed only at 12 weeks after shunt surgery. Pressure overload evoked short and biphasic activation of Akt at 15 min and 1 day after aortic banding. In contrast, volume overload induced sustained activation of Akt from 1 day to 1 week. Concordant phosphorylation of downstream targets of Akt, glycogen synthase kinase-3beta (GSK-3beta) and p70 ribosomal S6 kinase (p70(S6K)), in response to Akt activation was observed at 15 min after pressure overload. However in volume-overloaded hearts, phosphorylation of GSK-3beta and p70(S6K) was observed at 6 weeks and at 6 and 12 weeks, respectively, and was not coincident with Akt activation. These findings suggest that phosphorylation of GSK-3beta and p70(S6K) is regulated by an alternative pathway other than Akt in volume-overloaded hearts.
Conclusion:
Pressure and volume overload-induced cardiac hypertrophy is associated with distinct patterns of activation of signal transduction pathways. These data may suggest that stimulus-specific heterogeneity in the signaling pathway plays a role in determining the type of cardiac hypertrophy.
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