Contraction-Induced Cell Wounding and Release of Fibroblast Growth Factor in Heart

Abstract

The heart hypertrophies in response to certain forms of increased mechanical load, but it is not understood how, at the molecular level, the mechanical stimulus of increased load is transduced into a cell growth response. One possibility is that mechanical stress provokes the release of myocyte-derived autocrine growth factors. Two such candidate growth factors, acidic and basic fibroblast growth factor (aFGF and bFGF, respectively), are released via mechanically induced disruptions of the cell plasma membrane. In the present study, we demonstrate that transient, survivable disruption (wounding) of the cardiac myocyte plasma 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 sections indicated that an average of 25% of the myocytes contained cytosolic serum albumin; ie, this proportion had suffered a plasma membrane wound. Wounding frequency increased approximately threefold after beta-adrenergic stimulation of heart rate and force of contraction. Heparin-Sepharose chromatography, enzyme-linked immunosorbent assay, growth assay 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, beta-adrenergic stimulation of heart rate and force of contraction increased FGF release. Cell wounding is a fundamental but previously unrecognized aspect of the biology of the cardiac myocyte. We propose that contraction-induced cardiac myocyte wounding releases aFGF and bFGF, which then may act as autocrine growth-promoting stimuli.

Angiogenesis induced in muscle by a recombinant adenovirus expressing functional isoforms of basic fibroblast growth factor

“…Sublethal membrane wounding and release of cytosolic bFGF without cell necrosis have also been documented in vivo after strenuous or eccentric contraction of normal and dystrophic muscle or in contraction-induced cell wounding in the heart. 29,30 It is possible, although to date not formally proven, that the release of bFGF is particularly important in skeletal muscle and heart and is under the control of a physiological process. We have observed that levels of released bFGF are proportionally elevated in the conditioned medium of a myoblast cell The number of vessels staining positive in gastrocnemius muscle sections were counted under a Zeiss microscope (magnification ×200) and expressed in number per mm 2 (field surface = 0.74 mm 2 ).…”

Role of transiently altered sarcolemmal membrane permeability and basic fibroblast growth factor release in the hypertrophic response of adult rat ventricular myocytes to increased mechanical activity in vitro.

“…In the intact heart, we have documented increased release by ELISA of both bFGF and aFGF in the perfusate of adult rat hearts retrogradely perfused for 5 min ex vivo in a Langendorff preparation with a physiologic saline solution containing 10 Ϫ7 M isoproterenol (60). In confluent serum-starved neonatal rat ventricular myocytes as well as adult rat ventricular myocytes, addition of exogenous bFGF or aFGF induced activation of MAP kinase kinase (MEKs) as well as both 42-and 44-kD isotypes of MAPK (ERK2/ERK1) (10).…”

Mitsugumin 53 (MG53) facilitates vesicle trafficking in striated muscle to contribute to cell membrane repair

“…If entry of the oxidative environment is important in membrane resealing in many cell types, then modulation of the extracellular oxidative state could have therapeutic implications in a number of tissues where compromised membrane repair may be involved, including skeletal and cardiac muscles. 17,18 Additionally, the involvement of a ubiquitous binding target like PS in MG53 function could indicate that MG53 may be able to function in cell types other than muscle. If it can function in non-muscle cell types, MG53 could have significant therapeutic implications.…”