Inhibition of stretch-activated channels, disruption of the cytoskeleton, and arrest of contractile activity did not prevent stretch-induced immediate-early gene expression and hypertrophy in cardiac myocytes.
Mechanotransduction of stretch into hypertrophic gene expression in cardiac myocytes does not require Gd3+-sensitive stretch-activated channels, intact microtubules/microfilaments, or contractile activity.
Mechanical loading of cardiac and skeletal muscles in vivo and in vitro causes rapid activation of a number of immediate-early (IE) genes and hypertrophy of muscle cells. However, little is known as to how muscle cells sense mechanical load and transduce it into intracellular signals of gene regulation. We examined roles of putative cellular mechanotransducers, mechanosensitive ion channels, the cytoskeleton, and contractile activity in stretch-induced hypertrophy of cardiac myocytes grown on a deformable silicone sheet. Using the patch-clamp technique, we found a single class of stretch-activated cation channel that was completely blocked by gadolinium (Gd3+). Inhibition of this channel by Gd3+ did not affect either the stretch-induced expression of IE genes or the increase in protein synthesis. Neither disruption of microtubules with colchicine nor that of actin microfilaments by cytochalasin D prevented the stretch-induced IE gene expression and increase in protein synthesis. Arresting contractile activity of myocytes by high K+, tetrodotoxin, or Ba2+ did not affect the stretch-induced IE gene expression. Tetrodotoxin-arrested myocytes could increase protein synthesis in response to stretch. These results suggest that Gd(3+)-sensitive ion channels, microtubules, microfilaments, and contractile activity may not be necessary for transduction of mechanical stretch into the IE gene expression and hypertrophy. The stimulus of membrane stretch may be transmitted to the cell nucleus through some mechanisms other than electrical or direct mechanical transduction in cardiac myocytes.
Sadoshima et al. (1992) studied Cardiac hypertrophy (in vitro model). Gadolinium, colchicine, cytochalasin D, and tetrodotoxin vs. Control (no drug) was evaluated on Stretch-induced immediate-early gene expression and protein synthesis. Inhibition of stretch-activated channels, disruption of the cytoskeleton, and arrest of contractile activity did not prevent stretch-induced immediate-early gene expression and hypertrophy in cardiac myocytes.