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1 CIHR Group in Matrix Dynamics, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada
* To whom correspondence should be addressed. E-mail: jiaxu.wang{at}utoronto.ca.
The myocardium responds to chronic pressure or volume overload by activation and proliferation of cardiac fibroblasts and their differentiation into myofibroblasts. As 
-smooth muscle actin (SMA) expression is the classical marker for myofibroblast differentiation, we examined force-induced SMA expression and regulation by specific MAP kinase pathways. Rat cardiac fibroblasts were separated from myocytes and smooth muscle cells, cultured and phenotyped using SMA, vimentin, ED-A fibronectin and absence of desmin as myofibroblast markers. Static tensile forces (0.65 pN/µm2) were applied to fibroblasts via collagen-coated magnetite beads. In neonatal cardiac fibroblasts cultured for 1 day, immunostaining, Western and Northern blotting showed very low basal levels of SMA. After application of force there were 1.5-2 fold increases of SMA protein and mRNA within 4 hours. Force-induced SMA expression was dependent on ERK phosphorylation and on intact actin filaments. In contrast to cells cultured for 1 day, cells grown for 3 days on rigid substrates showed prominent stress fibers and high basal levels of SMA that were reduced by 32% within 4 hr after force application. ERK was not activated by force but p38 phosphorylation was required for force-induced inhibition of SMA expression. These results indicate that mechanical force-induced regulation of SMA content is dependent on myofibroblast differentiation and by selective activation of MAP kinases.
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