Fibroblast growth factor-2 mediates pressure-induced hypertrophic response
Jo El J. Schultz, … , Thomas R. Kimball, Thomas Doetschman
Jo El J. Schultz, … , Thomas R. Kimball, Thomas Doetschman
Published September 15, 1999
Citation Information: J Clin Invest. 1999;104(6):709-719. https://doi.org/10.1172/JCI7315.
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Article

Fibroblast growth factor-2 mediates pressure-induced hypertrophic response

Abstract

In vitro, fibroblast growth factor-2 (FGF2) has been implicated in cardiomyocyte growth and reexpression of fetal contractile genes, both markers of hypertrophy. However, its in vivo role in cardiac hypertrophy during pressure overload is not well characterized. Mice with or without FGF2 (Fgf2+/+ and Fgf2–/–, respectively) were subjected to transverse aortic coarctation (AC). Left ventricular (LV) mass and wall thickness were assessed by echocardiography preoperatively and once a week postoperatively for 10 weeks. In vivo LV function during dobutamine stimulation, cardiomyocyte cross-sectional area, and recapitulation of fetal cardiac genes were also measured. AC Fgf2–/– mice develop significantly less hypertrophy (4–24% increase) compared with AC Fgf2+/+ mice (41–52% increase). Cardiomyocyte cross-sectional area is significantly reduced in AC Fgf2–/– mice. Noncoarcted (NC) and AC Fgf2–/– mice have similar β-adrenergic responses, but those of AC Fgf2+/+ mice are blunted. A lack of mitotic growth in both AC Fgf2+/+ and Fgf2–/– hearts indicates a hypertrophic response of cardiomyocytes. Consequently, FGF2 plays a major role in cardiac hypertrophy. Comparison of α- and β-cardiac myosin heavy chain mRNA and protein levels in NC and AC Fgf2+/+ and Fgf2–/– mice indicates that myosin heavy chain composition depends on hemodynamic stress rather than on FGF2 or hypertrophy, and that isoform switching is transcriptionally, not posttranscriptionally, regulated.

Authors

Jo El J. Schultz, Sandra A. Witt, Michelle L. Nieman, Peter J. Reiser, Sandra J. Engle, Ming Zhou, Sharon A. Pawlowski, John N. Lorenz, Thomas R. Kimball, Thomas Doetschman

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Figure 2

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Serial echocardiographic results for Fgf2+/+ (open bars) and Fgf2–/– (fi...
Serial echocardiographic results for Fgf2+/+ (open bars) and Fgf2–/– (filled bars) mice before and after AC. All values are expressed as mean ± SEM. *P < 0.05 vs. prebanded. #P < 0.05 vs. Fgf2+/+ coarct. n = 6 for Fgf2+/+ and Fgf2–/–. (a) Calculated LV mass for prebanded and 1- to 10-week AC Fgf2+/+ and Fgf2–/– mice showed similar increases at 8 and 9 weeks, but by 10 weeks, that increase in LV mass was significantly less for Fgf2–/– compared with AC Fgf2+/+. LV mass was calculated from the echocardiographic measurements of SWT, PWT, and LVED. (b) Relative wall thickness (h/r) for prebanded and 1- to 10-week AC Fgf2+/+ and Fgf2–/– mice remained constant, indicating an eccentric form of cardiac hypertrophy during pressure overload. Relative wall thickness was extrapolated from the echocardiographic measurements of PWT and LVED. (c) Fractional shortening (FS) for prebanded and 1- to 10-week AC Fgf2+/+ and Fgf2–/– mice showed a preservation of function, suggesting a compensated stage of hypertrophy. FS was determined from the echocardiographic measurements of LVED and LVES.