Regulation of cardiomyocyte mechanotransduction by the cardiac cycle.
BACKGROUND
Overloading the left ventricle in systole (pressure overload) is associated with a distinct morphological response compared with overload in diastole (volume overload).


RESULTS
We designed a novel computer-controlled experimental system that interfaces biaxially uniform strain with electrical pacing, so that cellular deformation can be imposed during a specified phase of the cardiac cycle. Cardiomyocytes were exposed to strain (4%) during either the first third (systolic phase) or last third (diastolic phase) of the cardiac cycle. Strain imposed during the systolic phase selectively activated p44/42 mitogen-activated protein kinase (MAPK) and MAPK/extracellular signal-regulated protein kinase kinase (MEK1/2, an activator of p44/42 MAPK) compared with strain imposed during the diastolic phase. In contrast, there was no difference in activation of p38 and c-Jun NH(2)-terminal kinases induced by strain imposed during the systolic phase (5.8- and 3.3-fold versus control, n=4) compared with the diastolic phase (5.5- and 3.1-fold). Induction of both brain natriuretic peptide (5.8-fold versus control, P:<0.05, n=3) and tenascin-C (7.0-fold, P:<0.02) mRNA expression by strain imposed during the systolic phase was greater than during the diastolic phase (3.9- and 3.6-fold, respectively). [(3)H]leucine incorporation induced by strain imposed during the systolic phase (4.0-fold versus control) was greater than during the diastolic phase (2.7-fold, P:<0.02, n=4); a selective inhibitor of MEK1/2 inhibited this difference.


CONCLUSIONS
Mechanical activation of p44/42 MAPK and MEK1/2, gene expression, and protein synthesis is regulated by the cardiac cycle, suggesting that mechanotransduction at the cellular level may underlie differences between pressure and volume overload of the heart.
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
K
K
Yamamoto
Q N
QN
Dang
Y
Y
Maeda
H
H
Huang
R A
RA
Kelly
R T
RT
Lee
D000818:Animals; D001696:Biomechanical Phenomena; D015870:Gene Expression; D006321:Heart / Q000502:physiology; D066298:In Vitro Techniques; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000096:biosynthesis / Q000235:genetics; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017725:Ventricular Pressure / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases
D020097:Natriuretic Peptide, Brain; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases