Transforming growth factor-s, (TGF-fl1) is a peptide growth factor that may play a role in the myocardial response to hypertrophic stimuli. However, the cellular distribution, mechanism of induction, and source of increased TGF-fi1 in response to hypertrophic stimuli are not known.We tested the hypothesis that the cardiac myocyte responds to hypertrophic stimuli with the increased expression of TGF-,31. In adult rat ventricular myocardium freshly dissociated into myocyte and nonmyocyte cellular fractions, the preponderance of TGF-p1 mRNA visualized by Northern hybridization was in the nonmyocyte fraction. Abdominal aortic constriction (7 d) and subcutaneous norepinephrine infusion (36 h) each caused ventricular hypertrophy associated with 3.1-fold and 3.8-fold increases, respectively, in TGF-fl1 mRNA in the myocyte fraction, but had no effect on the level of TGF-/31 mRNA in the nonmyocyte fraction. In ventricular myocytes, norepinephrine likewise caused a 4.1-fold increase in TGF-fi1 mRNA associated with an increase in TGF-P bioactivity. This induction of TGF-f31 mRNA occurred at norepinephrine concentrations as low as 1 nM and was blocked by prazosin, but not propranolol.NE did not increase the TGF-P1 mRNA level in nonmyocytes, primarily fibroblasts, cultured from neonatal rat ventricle. Thus, the cardiac myocyte responds to two hypertrophic stimuli, pressure overload and norepinephrine, with the induction of TGF-81. These data support the view that TGF-.81, released by myocytes and acting in an autocrine and/or paracrine manner, is involved in myocardial remodeling by hypertrophic stimuli. (J. Clin. Invest. 1994.
One of the trophic factors that has been implicated in initiating or facilitating growth in response to increased mechanical stress in several tissues and cell types is basic fibroblast growth factor (bFGF; FGF-2). Although mammalian cardiac muscle cells express bFGF, it is not known whether it plays a role in mediating cardiac adaptation to increased load, nor how release of the cytosolic 18-kD isoform of bFGF would be regulated in response to increased mechanical stress. To test the hypothesis that increased mechanical activity induces transient alterations in sarcolemmal permeability that allow cytosolic bFGF to be released and subsequently to act as an autocrine and paracrine growth stimulus, we examined primary isolates of adult rat ventricular myocytes maintained in serum-free, defined medium that were continually paced at 3 Hz for up to 5 d. Paced myocytes, but not nonpaced control cells, exhibited a "hypertrophic" response, which was characterized by increases in the rate of phenylalanine incorporation, total cellular protein content, and cell size. These changes could be mimicked in control cells by exogenous recombinant bFGF and could be blocked in continually paced cells by a specific neutralizing anti-bFGF antibody. In addition, medium conditioned by continually paced myocytes contained significantly more bFGF measured by ELISA and more mitogenic activity for 3T3 cells, activity that could be reduced by a neutralizing anti-bFGF antibody. The hypothesis that transient membrane disruptions sufficient to allow release of cytosolic bFGF occur in paced myocytes was examined by monitoring the rate of uptake into myocytes from the medium of 10-kD dextran linked to fluorescein. Paced myocytes exhibited a significantly higher rate of fluoresceinlabeled dextran uptake. These data are consistent with the hypothesis that nonlethal, transient alterations in sarcolemmal membrane permeability with release of cytosolic bFGF is one mechanism by which increased mechanical activity could lead to a hypertrophic response in cardiac myocytes.( J. Clin. Invest. 1996. 97:281-291.)
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