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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062943-02
Application #
6390406
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Reinlib, Leslie
Project Start
2000-04-24
Project End
2001-12-31
Budget Start
2001-04-01
Budget End
2001-12-31
Support Year
2
Fiscal Year
2001
Total Cost
$187,977
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Wang, Yanlin; De Keulenaer, Gilles W; Weinberg, Ellen O et al. (2002) Direct biomechanical induction of endogenous calcineurin inhibitor Down Syndrome Critical Region-1 in cardiac myocytes. Am J Physiol Heart Circ Physiol 283:H533-9
Yamamoto, K; Dang, Q N; Maeda, Y et al. (2001) Regulation of cardiomyocyte mechanotransduction by the cardiac cycle. Circulation 103:1459-64
Lee, R; Collins, T (2001) Nuclear factor-kappaB and cell survival: IAPs call for support. Circ Res 88:262-4