Myocardial mechanical overload may be broadly categorized as """"""""pressure"""""""" overload (mechanical overload in systole) or volume overload (mechanical overload in diastole). Pressure overload and volume overload are associated with distinct morphologic and molecular responses. At the molecular level, differences between these two types of mechanical overload have been incompletely described. In vitro experiments indicate that mechanotransduction responses are preserved in cultured cardiomyocytes. Until now, these experiments have generally been performed by stretching cardiomyocytes with no control of the cardiac cycle, an approach that does not allow distinction between mechnical overload in contraction vs. relaxation. Here we describe a unique system that allows precisely controlled mechnical strains as well as electrical pacing in cultured cardiomyocytes. We can now impose a cellular deformation at a specified period relative to the cardiac cycle. We propose exploring the molecular responses of cultured cardiomyocytes in this unique in vitro model to identify cardiomocyte mechanotransduction mechanisms regulated by the cardiac cycle.
The Aims of this proposal are:
Aim 1 : We will test the hypothesis that biaxial strain applied during contraction of the cardiac myocyte leads to more protein synthesis and differences in cell shape compared to strain applied during relaxation.
Aim 2 : We will test the hypothesis that MAP kinase intracellular signaling pathways (i.e., ERK, JNK and p38) are differently activated by biaxial strain applied during contraction of the cardiac myocyte compared to strain applied during relaxation of the myocyte.
Aim 3 : We will test the hypothesis that specific genes are differently activated by biaxial strain applied during contraction of the cardiac myocyte compared to strain applied during relaxation of the myocyte.
Aim 4 : We will explore differences in the transcriptional profiles of cardiomyocytes stimulated mechanically during contraction vs. relaxation using DNA microarray technology.
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