CONTRACTION-INDUCED CELL WOUNDING AND RELEASE OF FIBROBLAST GROWTH-FACTOR IN HEART

The heart hypertrophies in response to certain forms of increased mech anical load, but it is not understood how, at the molecular level, the mechanical stimulus of increased load is transduced into a cell growt h response. One possibility is that mechanical stress provokes the rel ease of myocyte-derived autocrine growth factors. Two such candidate g rowth factors, acidic and basic fibroblast growth factor (aFGF and bFG F, respectively), are released via mechanically induced disruptions of the cell plasma membrane. In the present study, we demonstrate that t ransient, survivable disruption (wounding) of the cardiac myocyte plas ma membrane is a constitutive event in vivo. Frozen sections of normal rat heart were immunostained to reveal the distribution of the wound event marker, serum albumin. Quantitative image analysis of these sect ions indicated that an average of 25% of the myocytes contained cytoso lic serum albumin; ie, this proportion had suffered a plasma membrane wound. Wounding frequency increased approximately threefold after P-ad renergic stimulation of heart rate and force of contraction. Heparin-S epharose chromatography, enzyme-linked immunosorbent assay, growth ass ay coupled with antibody neutralization, and two-dimensional SDS-PAGE followed by immunoblotting were used to demonstrate that both aFGF and bFGF were released from an ex vivo beating rat heart. Importantly, P- adrenergic stimulation of heart rate and force of contraction increase d FGF release. Cell wounding is a fundamental but previously unrecogni zed aspect of the biology of the cardiac myocyte. We propose that cont raction-induced cardiac myocyte wounding releases aFGF and bFGF, which then may act as autocrine growth-promoting stimuli.