Search

Background— Although cellular redox balance plays an important role in mechanically induced cardiac hypertrophy, the mechanisms of regulation are incompletely defined. Because thioredoxin is a major intracellular antioxidant and can also regulate redox-dependent transcription, we explored the role of thioredoxin activity in mechanically overloaded cardiomyocytes in vitro and in vivo. Methods and Results— Overexpression of thioredoxin induced protein synthesis in cardiomyocytes (127±5% of controls, P P P P P P P Conclusions— Thus, even though thioredoxin is an antioxidant, activation of thioredoxin participates in the development of pressure-overload cardiac hypertrophy, demonstrating the dual function of thioredoxin as both an antioxidant and a signaling protein. These results also support the emerging concept that the thioredoxin inhibitor Txnip is a critical regulator of biomechanical signaling.

Cells respond to mechanical stimuli with diverse molecular responses. The nature of the sensory mechanism involved in mechanotransduction is not known, but integrins may play an important role. The integrins are linked to both the cytoskeleton and extracellular matrix, suggesting that probing cells via integrins should yield different mechanical properties than probing cells via non–cytoskeleton-associated receptors. To test the hypothesis that the mechanical properties of a cell are dependent on the receptor on which the stress is applied, human aortic smooth muscle cells were plated, and magnetic beads, targeted either to the integrins via fibronectin or to the transferrin receptor by use of an IgG antibody, were attached to the cell surface. The resistance of the cell to deformation (“stiffness”) was estimated by oscillating the magnetic beads at 1 Hz by use of single-pole magnetic tweezers at 2 different magnitudes. The ratio of bead displacements at different magnitudes was used to explore the mechanical properties of the cells. Cells stressed via the integrins required ≈10-fold more force to obtain the same bead displacements as the cells stressed via the transferrin receptors. Cells stressed via integrins showed stiffening behavior as the force was increased, whereas this stiffening was significantly less for cells stressed via the transferrin receptor ( P

Background —Overloading the left ventricle in systole (pressure overload) is associated with a distinct morphological response compared with overload in diastole (volume overload). Methods and 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 P 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 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.

Background —Increased biomechanical stresses in the fibrous cap of atherosclerotic plaques contribute to plaque rupture and, consequently, to thrombosis and myocardial infarction. Thin fibrous caps and large lipid pools are important determinants of increased plaque stresses. Although coronary calcification is associated with worse cardiovascular prognosis, the relationship between atheroma calcification and stresses is incompletely described. Methods and Results —To test the hypothesis that calcification impacts biomechanical stresses in human atherosclerotic lesions, we studied 20 human coronary lesions with techniques that have previously been shown to predict plaque rupture locations accurately. Ten ruptured and 10 stable lesions derived from post mortem coronary arteries were studied using large-strain finite element analysis. Maximum stress was not correlated with percentage of calcification, but it was positively correlated with the percentage of lipid ( P =0.024). When calcification was eliminated and replaced with fibrous plaque, stress changed insignificantly; the median increase in stress for all specimens was 0.1% (range, 0% to 8%; P =0.85). In contrast, stress decreased by a median of 26% (range, 1% to 78%; P =0.02) when lipid was replaced with fibrous plaque. Conclusions —Calcification does not increase fibrous cap stress in typical ruptured or stable human coronary atherosclerotic lesions. In contrast to lipid pools, which dramatically increase stresses, calcification does not seem to decrease the mechanical stability of the coronary atheroma.