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Cardiovascular Research 2004 63(3):458-466; doi:10.1016/j.cardiores.2004.04.024
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Copyright © 2004, European Society of Cardiology

Fibroblast growth factor 2 isoforms and cardiac hypertrophy

Elissavet Kardami*, Zhi-Sheng Jiang, Sarah K Jimenez, Cheryl J Hirst, Farah Sheikh, Peter Zahradka and Peter A Cattini

Institute of Cardiovascular Sciences 3008, St. Boniface Research Centre and Departments of Human Anatomy and Cell Sciences and Physiology, 351 Tache Ave., University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6

* Corresponding author. Tel: +204-235-3519; fax: +204-233-6723. Email address: ekardami{at}sbrc.ca

Received 26 January 2004; revised 30 March 2004; accepted 20 April 2004


   Abstract
Top
 Abstract
1. Introduction
 2. FGF-2
 3. FGF-2 in cardiac...
 4. Concluding remarks
 References
 
Fibroblast growth factor 2 (FGF-2), a multifunctional polypeptide that affects cell growth and differentiation and becomes upregulated by stress, is expressed as AUG-initiated 18 kDa FGF-2 or CUG-initiated 21–34 kDa (hi-FGF-2) isoforms. Animal models have provided strong evidence that FGF-2 is essential for the manifestation of overload- and angiotensin-induced cardiac hypertrophy. Nevertheless, studies to-date have not discriminated between the activities of 18 kDa FGF-2 and hi-FGF-2. Our recent work has pointed to a potent pro-hypertrophic effect of added hi-FGF-2, and a pro-apoptotic effect of sustained intracrine hi-FGF-2 signaling. In the future, it will be important to differentiate between the activities of the different FGF-2 isoforms in the context of adaptive and maladaptive myocardial hypertrophy and heart failure. Based on all available evidence, we propose that while the 18-kDa FGF-2 is a component of an adaptive trophic response, a switch to hi-FGF-2 accumulation would exacerbate hypertrophy and contribute to cell death, thus driving the myocardium towards a maladaptive phenotype.

KEYWORDS Cardiac hypertrophy; FGF-2 signal transduction; Intracrine signaling; CUG-FGF-2


   1. Introduction
Top
 Abstract
 1. Introduction
2. FGF-2
 3. FGF-2 in cardiac...
 4. Concluding remarks
 References
 
Cardiac hypertrophy occurs in response to a variety of physiological and pathophysiological stimuli and is believed to represent at least at its onset a compensatory response so that the heart can meet altered functional demands [1,2]. It is characterized by increased cardiac mass relative to body weight, reflected also in the increased size of individual cardiomyocytes. Hypertrophy has been broadly categorized as ‘good’ or adaptive, such as exercise induced hypertrophy and compensated hypertrophy in response to hemodynamic load, or ‘bad’ and maladaptive occurring in response to prolonged and unresolved hemodynamic stress and in various cardiomyopathies; it is a major predictor for the development of heart failure [1,2]. Understanding the molecular triggers and mechanisms leading to the various types of myocardial hypertrophy is essential to allow proper management at the clinic. This may include prevention or reduction of the trophic response, or selective interference with specific elements of ‘toxic’ signal transduction pathways. The reader is directed to several recent comprehensive reviews on diverse aspects of the topic [2–7].

Currently, growth promoting factors such as angiotensin (Ang-II), endothelin (ET-1), members of the interleukin-6 (IL-6) family of proteins, insulin-like growth factor-1 and others have been identified as direct triggers of a hypertrophic response at the level of the cardiomyocyte [2]. There is increasing evidence that FGF-2, an endogenous and multifunctional protein is also a ‘player’ in this context [8]. To better understand its potential, we will provide an up-to-date overview of the properties of FGF-2, in general and in relation to cardiac hypertrophy. For the purposes of this review, the terms cardiac- and cardiomyocyte hypertrophy are used to describe the increase in adult heart and cardiomyocyte mass and size subsequent to stimulation of protein (including myofibrillar protein) and RNA synthesis in response to hemodynamic and/or trophic stimuli.


   2. FGF-2
Top
 Abstract
 1. Introduction
 2. FGF-2
3. FGF-2 in cardiac...
 4. Concluding remarks
 References
 
FGF-2 is a ubiquitous polypeptide and a well studied member of a large family of heparin binding growth factors [9]. It can be found in 18 kDa, and 21–34 kDa forms, deriving from alternate translation initiation sites. AUG-sites produce the 18-kDa protein, while several CUG-start sites produce the larger FGF-2 species [10] collectively referred to by us as hi-FGF-2. The vast majority of studies to-date have described the effects of 18 kDa FGF-2, since this isoform is released to the extracellular space from where it can access plasma membrane receptors. Nevertheless, there is increasing evidence that hi-FGF-2 needs to be reckoned with, having distinct and sometimes opposing effects to the 18-kDa isoform [11]. Best studied as a potent mitogen for cells of mesodermal and neuroectodermal origin and a powerful angiogenic agent, FGF-2 is multifunctional, promoting cell survival in many cell types, and affecting differentiation and gene expression [9]. Its expression is upregulated during stress and injury [12]. FGF-2 promotes DNA, RNA and protein synthesis of cardiomyocytes and has powerful cardioprotective properties [8].

FGF-2 accumulation is regulated at the transcriptional and translational level but also at the level of ‘bioavailability’. In the latter case, FGF-2 is retained locally by binding to heparan sulphate proteoglycans (HSPGs) at the extracellular matrix and at the cell surface [9]. It is believed that thus retained FGF-2 becomes available for interaction and activation of cell receptors after specific stimuli (injury, heparinase activity) release it from its ‘storage sites’ [8]. Multiple agents including Ang-II, ET-1, and FGF-2 itself stimulate FGF-2 gene expression [8,13]. Most mechanisms implicate protein kinase C (PKC) activation and/or the intracellular second messenger, cyclic AMP [14]. Multiple putative transcription factor binding sites are present within the proximal promoter region of both the human and rat FGF-2 genes: these include GC-rich stimulating protein 1 (Sp1) and early growth response-1 protein (Egr-1) sites [8]. Egr-1 has been implicated in the phenylephrine-induced stimulation of FGF-2 promoter activity [15] as well as FGF-2 auto-regulation [13].

Expression of FGF-2 is regulated at the translational level by several cis-acting elements of the RNA leader sequence [16,17]. A non-classical mechanism of translation occurs via an internal ribosome entry process, due to the presence of internal ribosome entry sites (IRES) in the mRNA sequence of FGF-2. The human FGF-2 mRNA contains four CUG and one AUG translation initiation codons [18]. Only the 5' end proximal CUG codon, producing the 34-kDa isoform uses a cap-dependent mechanism of translation, while the remaining four can all be initiated by a single IRES [19]. Cap- but not IRES-dependent translation is inhibited under stress conditions such as ischemia and thus IRES-mediated translation is proposed to result in FGF-2 accumulation in stressed cells [17].

FGF-2 release to the extracellular environment can occur via an energy-dependent and Golgi independent mechanism [9]. Lethal as well as non-lethal plasma membrane disruption also lead to FGF-2 release[9]. Adult cardiomyocytes and hearts release FGF-2 on a beat to beat basis [20], and increased contractility [21] or increased expression of FGF-2 [22] results in increased FGF-2 release. An implicit assumption in most studies is that only the 18-kDa FGF-2 species is released by the cells. A small number of studies, however, report presence of hi-FGF-2 in the extracellular space (summarized in Ref. [7]). Recently, a new mechanism of energy-dependent FGF-2 export via shed vesicles, budding off from the plasma membrane, was reported [23] and all FGF-2 isoforms were present in shed-vesicle-mediated export [23]. Certain condition such as heat shock and estrogen receptor activation may promote preferential release of hi-FGF-2 [11].

Many of the effects of FGF-2 are mediated by binding and activating high affinity plasma membrane tyrosine kinase receptors (FGFR) as well as HSPGs, acting as lower affinity receptors [9]. FGFR is found in most cells and tissues and has four major members (FGFR1–4).[24]. FGFR1 is the predominant FGFR in embryonic, neonatal and adult cardiomyocytes [25–27]. Binding of FGF-2 activates FGFR and major signal transduction pathways such as all three branches of the mitogen-activated protein kinase (MAPK) pathway (via Ras activation), the phosphoinositide/PKC pathway and Src-associated pathways [8,24]. FGF-2 activates extracellular signal regulated kinases (ERKs), p38 as well as c-jun N-terminal kinases (JNKs) [28] in a number of cell types, including neonatal and adult cardiomyocytes [22,29]. Several signals located downstream of FGF-2-FGFR have been linked to the induction of hypertrophy: These include ERKs, p38, PKC, increased cytosolic calcium as well as glycogen synthase kinase-3, GSK-3, [1,30–33] (Fig. 1). The ERK1/2 pathway was sufficient to induce hypertrophy in vivo [34]. Activated ERK1/2 translocates to the nucleus where it phosphorylates transcription factors that affect gene expression linked to the hypertrophic response. These include immediate early genes and the transcription factor GATA4 [34] known to regulate expression of many cardiac structural and hypertrophy-induced genes [2,33]. FGF-2 activates p38 [28] which may also contribute to hypertrophy by activating the transcription factor myocyte enhancer factor 2 (MEF2) [35]. In addition, p38 is required for the FGF-2-induced upregulation of IL-6 expression in non-muscle cells [36]. The IL-6 family of cytokines, acting via the plasma membrane gp130 signal transducer, can induce myocardial hypertrophy, as well as cardioprotection [1]. FGF-2-FGFR1 signal transduction leads to increased cytosolic and nuclear calcium in cardiomyocytes via the phospholipase C (PLC) pathway [37] resulting in activation of calcium dependent PKCs such as PKC{alpha} [29,38], and, potentially, activation of calmodulin [39] and the phosphatase calcineurin [40]. Calcium-dependent signaling plays a central role in overload hypertrophy [2,41]. Calcineurin induces hypertrophy by dephosphorylating transcription factors of the nuclear factor of activated T-cells (NFAT) group, resulting in its nuclear translocation and activation of hypertrophy-related genes [2,33]. The PKC isoforms {alpha} and {varepsilon}, activated by FGF-2 in cardiomyocytes, have been linked to the induction of hypertrophy [30,31]. PKC{zeta}, also activated by FGF-2, associates with and regulates the phosphorylation of p70 ribosomal S6 protein kinase (p70S6K) [42] that stimulates translation of a class of mRNAs that encode many of the components of the protein synthetic apparatus [43]. Activation of p70S6K by FGF-2 has been documented [44]. Furthermore, PKC activation as well as FGF-2 triggered signaling can result in the inactivation of the GSK-3 [45] in non-muscle cells and may play a similar role in myocytes. Active GSK-3 inhibits hypertrophy in response to diverse stimuli [2,46]. A third major pathway activated by plasma membrane FGFR1 includes interaction/activation of the tyrosine kinase Src [9]. Src proceeds to phosphorylate focal adhesion kinase (FAK) that was shown to mediate stretch- or ET-1-induced cardiomyocyte growth [47]. Src is also an integral component of G-coupled protein receptor (GCPR) signaling and can transactivate receptor tyrosine kinases: Src-mediated transactivation of the EGF receptor is required for the Ang-II-induced cardiac hypertrophy [48]. Whether there is a similar requirement for receptor transactivation by FGF-2 or of the FGFR by GCPR has yet to be determined. Major hypertrophy-related signaling pathways that are also linked to plasma membrane FGFR1-FGF-2 signal transduction are summarized in Fig. 1.


Figure 1
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  		Fig. 1 Plasma membrane triggered FGF-2-FGFR1 signal transduction. Solid lines show FGF-2 pathways documented in cardiomyocytes and related to hypertrophic growth [2,33]. Broken lines show hypertrophy-related pathways activated by FGF-2 in many other cell types. Following FGFR1 activation by FGF-2 at the plasma cell membrane, the Ras-, PLC-, and Src-dependent pathways are activated. Downstream signals include: ERK1/2, p38 and JNK, PKC and calcium-dependent signaling (calmodulin, calmodulin-dependent kinase=CaMK, calcineurin, PKC{alpha}). The CaMK pathway leads to the activation of histone deacetylase (HDAC) and the transcription factor MEF2 [2,33]. The PKC pathway can lead to activation of P70S6K and the upstream binding factor (UBF) necessary for increased rRNA synthesis [58], as well as to the phosphorylation and inactivation of GSK-3, allowing activation of the transcription factor NFAT [2,33]. GATA4, MEF2 and NFAT promote transcription of cardiac hypertrophy-associated genes [2,33].

 
Internalization and nuclear translocation of the FGF-2-FGFR1 complex, followed by direct interaction/activation of a number of genes with nuclear FGFR1 has been reported [49,50]. Exclusively intracrine FGF-2-FGFR1 has also been documented [51]: FGFR1 at the Golgi is released to the cytosol and, although it lacks a nuclear localization signal (NLS), is ‘carried’ to the nucleus via an importin β-mediated pathway [50] likely due to its interaction with hi-FGF-2. It is proposed that importin β recognizes the N-extension of hi-FGF-2 (acting as an NLS) [51]. A number of hormones, neurotransmitters, growth factors and second messengers activate the nuclear accumulation of FGFR1 in non-muscle cells [51] and may do so in cardiac cells. Nuclear FGF-2-FGFR1 signaling is summarized in Fig. 2.


Figure 2
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  		Fig. 2 Proposed intracrine FGF-2 signal transduction: A variety of pro-hypertrophic stimuli activate pathways that lead to: release of intracellular FGFR1 from the Golgi, binding to hi-FGF-2 (hiF) followed by nuclear transport via importin β. In the nucleus, FGFR1 (and hi-FGF-2) can be found in nuclear matrix structures associated with active transcription, including polymerase II (Pol II). FGFR1 can bind and activate the promoter of various genes including the FGF-2 gene [51]. Pro-growth signals can also lead to translokin-mediated nuclear translocation of the 18 kDa FGF-2 (18F) [55] that can be found in the nucleolus where it promotes nucleolin phosphorylation (via CK2) and rRNA synthesis.

 
Both 18 kDa and hi-FGF-2 localize to the nucleus of many cell types, including cardiomyocytes, where they exert direct as well as isoform specific effects [52,53]. Not only the N-terminal extension of hi-FGF-2, but also specific amino acids within the common 18 kDa sequence, mediate nuclear localization/ translocation [54]. Extracellular 18 kDa FGF-2 translocates to the nucleus/nucleolus during the transition from quiescence to G1, following an incompletely understood mechanisms that requires binding of FGF-2 to the cytosolic protein translokin [55]. Nuclear translocation, as well as the ability of nuclear 18 kDa FGF-2 to interact with and activate casein kinase 2 (CK2), are essential for its mitogenic effect [44,55]. Mutant versions of 18 kDa FGF-2 unable to bind translokin and thus unable to translocate to the nucleus, or unable to bind/activate CK2 despite the activation of FGFR1 and nuclear translocation, are no longer mitogenic [44]. FGF-2-dependent CK2 activation leads to the phosphorylation of the nucleolar protein nucleolin, and the activation of rRNA transcription [56,57]. It is important to note that stimulation of rRNA transcription, leading to ribosome biogenesis, is not only required for cell duplication in anticipation of mitotic division, but also for the maintenance of cardiac hypertrophy [58]. Hi-FGF-2 does not interact with the translokin system [55], it is however transported to the nucleus by its N-terminal extension [10]. Studies from stable cell lines, obtained on the basis of their ability to survive hi-FGF-2 overexpression, have proposed that hi-FGF-2 confers a transformed phenotype [10]. Studies using transient gene transfer on the other hand have shown that, unlike 18 kDa FGF-2, prolonged nuclear accumulation of hi-FGF-2 causes mitotic arrest, binucleation and eventually cell death in cardiomyocytes [53,59,60], HEK293 cells (our unpublished observations) and neuronal cells [61].


   3. FGF-2 in cardiac hypertrophy
Top
 Abstract
 1. Introduction
 2. FGF-2
 3. FGF-2 in cardiac...
4. Concluding remarks
 References
 
The potential of FGF-2 to induce hypertrophy was first inferred from in vitro studies where it was shown to stimulate expression of fetal genes such as β-myosin heavy chain, {alpha}-skeletal muscle actin and atrial natriuretic factor that are also re-expressed in pressure overload hypertrophy [62]. Compelling evidence by Kaye et al. [21] linked FGF-2 to hypertrophic growth of isolated adult myocytes: in addition to showing that added FGF-2 (the 18-kDa species) increased protein synthesis and myocyte size, they demonstrated that endogenous FGF-2 (of unknown isoform composition), released by paced myocytes [20] was also essential for the hypertrophic response [21]. The trophic effect of human pericardial fluid from patients undergoing surgery was due at least in part to its high FGF-2 content [63].

FGF-2-deficient mouse models have been used to examine the role of FGF-2 on normal and hypertrophic growth [64,65]. One such model presented normal cardiac growth and function [65], while another, in a different genetic background, displayed cardiac dilatation and reduced function [64]. Other FGF-2-deficient mouse models [66,67] have not provided detailed information as to their cardiac phenotype in relation to growth or dilatation. The case for lack of FGF-2 involvement in normal post-natal growth is however strengthened by a different study showing that overexpression of the 18-kDa FGF-2 in the normal, non-stressed mouse heart does not cause hypertrophy [22]. Irrespectively of its precise effects during normal heart development, FGF-2 is essential for the development of pressure overload or Ang-II hypertrophy. Schultz et al. [65] demonstrated a significantly decreased ability for FGF-2-deficient mice to undergo cardiac hypertrophy in response to transverse aortic coarctation. Similarly, myocardial hypertrophy, but not hypertension, failed to develop in response to Ang-II in a different FGF-2-deficient model [64]. Other investigators [68] used rats overexpressing human renin and Ang-II genes resulting in high local Ang-II release and hypertension to show a strong correlation between the hypertrophic phenotype and increased expression of FGF-2, of unknown isoform composition. Aldosterone inhibition furthermore reversed both the increase in FGF-2 and cardiac hypertrophy [68] supporting a cause and effect relationship. Finally, FGF-2-overexpressing hearts had an exaggerated hypertrophic response to isoproterenol, suggesting a direct hypertrophic effect of FGF-2 on cardiomyocytes [22].

These models have not discriminated between the roles of the 18 kDa versus the hi-FGF-2 species, although all are expressed in the heart [69,70]. In the case of FGF-2-deficient mice, all FGF-2 isoforms are removed and thus they are all candidates for mediating the hypertrophic response. Even in the case of 18 kDa FGF-2 overexpression in the heart, some of the observed effects may have been caused by hi-FGF-2 due to the upregulation of endogenous hi-FGF-2; see the first figure in Ref. [22]. In studies on endogenous FGF-2 expression, FGF-2 levels are assessed by enzyme-linked immunoabsorbent assays using antibodies that cannot discriminate between the isoforms. In addition, the exact FGF-2 isoform composition may be in question even in those cases where detection of FGF-2 is achieved by Western blotting: the N-terminal extension of hi-FGF-2 is vulnerable to limited degradation during tissue extraction, producing the 18-kDa isoform [71]. We have found that the addition of recombinant hi-FGF-2 (but not of the 18-kDa isoform; not shown) to neonatal myocyte cultures induces a 40% increase in cell size (Fig. 3). We have also obtained in vivo evidence linking hi-FGF-2 to hypertrophy: Intracardiac administration of hi-FGF-2 to the ischemic left ventricle during the development of myocardial infarction (MI) subsequent to permanent coronary occlusion in a rat model resulted in significant heart and cardiomyocyte hypertrophy of the viable myocardium, reaching a 40% increase in the ratio of left ventricle to body weight at 6–8 weeks post MI . This hypertrophic response was also reflected at the level of the cardiomyocyte (Fig. 3) and since it occurred despite the reduction in infarct size in hi-FGF-2-treated hearts it is not a consequence of increased tissue loss [72]. We are currently investigating the mechanism of this phenomenon. Hi-FGF-2, like the 18-kDa protein, binds to and is retained by basal lamina and extracellular matrix at and around the site(s) of injection, from where it can access cell surface FGFR1 to activate downstream signals. Because hi-FGF-2 can induce expression of IL-6 [10], and the IL-6 group of proteins, acting via the gp130 signal transducer, is hypertrophic [1], we speculated that hi-FGF-2 might be upregulating a gp130-dependent axis. Indeed, levels of CT-1 (a IL-6-like molecule) and gp130 were significantly elevated in the hi-FGF-2 group (but not the 18-kDa-FGF-2 group; unpublished observations) at 2 weeks post-MI, prior to the development of statistically significant hypertrophy, suggesting that they may be a component of the mechanism of the observed response. The physiological significance of these findings is not yet clear since hi-FGF-2 is not normally exported by cells. Nevertheless, cardiac hi-FGF-2 increases transiently after isoproterenol-induced cardiac injury [73], and recent reports indicated that it can be ‘exported’ together with the 18-kDa species [23]; in fact, certain situations might promote hi-FGF-2 release preferentially [11].


Figure 3
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  		Fig. 3 Hi-FGF-2 induces cardiomyocyte hypertrophy. (A) Neonatal rat cardiomyocytes, maintained in culture for 2 days in a low serum medium, were treated with 10 ng/ml of recombinant human hi-FGF-2 and examined, by morphometry (Sigma ScanPro photographic analysis software), for size changes 2 days later. A total of 300 cells (in three different coverslips) were assessed in each group. Treated cells displayed significant (P<0.05) increase in surface area compared to untreated or 18 kDa-treated (not shown) cells. (B–C) Transverse sections from the viable left ventricle from (B) saline- or (C) hi-FGF-2-treated infarcted hearts, at 6 weeks post infarction. Myocytes, outlined by wheat germ agglutinin staining (as in Ref. [65]), are larger in the hi-FGF-2 group. Methods: Exactly as described previously [38] for the 18-kDa FGF-2. Hi-FGF-2 (2 µg) or saline were directly injected into the ischemic myocardium within 10 min from irreversible coronary occlusion. Bar=50 µm.

 
In addition to potential release from cells (a prerequisite for plasma membrane to nucleus signal transduction) hi-FGF-2 is likely an important effector of intracrine signaling (from cytosol to nucleus). Pro-hypertrophic agents (Ang-II, ET-1) and second messengers (PKC, cAMP) upregulate the intracrine hi-FGF-2-FGFR1-pathway that culminates in the induction of several other genes, including the FGF-2 gene [74,75] in adrenal medulla cells [51]. We have found that an intracrine-nuclear hi-FGF-2-FGFR1 signaling pathway is operating in cultured neonatal cardiomyocytes independently of the plasma membrane FGFR1 pathway [53]. High expression of hi-FGF-2 (but not 18 kDa FGF-2) causes chromatin compaction [53] leading to cell death presenting apoptotic features [59]. This effect is dose and time dependent [59], requires nuclear localization of hi-FGF-2, it is not prevented by neutralizing antibodies that block extracellular FGF-2, but is fully reversed by a kinase-deficient FGFR1, and by inhibition of the ERK1/2 pathway (unpublished observations). Our data to-date therefore point to an intracrine/nuclear hi-FGF-2-FGFR1-ERK1/2 pathway in cardiac myocytes, prolonged overstimulation of which leads to cell death [59]. We suggest that this pathway, activated by a variety of pro-hypertrophic and stress stimuli over time, is a candidate for contributing to development of maladaptive hypertrophy and heart failure.

It is important to emphasize that the effects of extracellular hi-FGF-2, initiating the plasma-membrane FGFR1 pathway and leading to an increase in size, are different than those of overexpressed hi-FGF-2 where the intracellular FGFR1 pathway leading to cell death would be more prominent. The potential for an active nuclear FGFR1-mediated pathway in adult cardiomyocytes is indicated by the presence of FGFR1 in the nucleus, in situ (Fig. 4). As a reminder, FGF-2 is also present at various cellular sites, in association with the nucleus and plasma membrane of cardiac myocytes as well as non-muscle cells (Fig. 4).


Figure 4
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  		Fig. 4 Nuclear localization of (A) FGFR1 and (B) FGF-2 (all isoforms), in transverse ventricular sections from an adult rat heart. (A) Triple fluorescence staining for FGFR1 (rabbit polyclonal antibodies, staining ‘green’ by fluorescein fluorescence), β-catenin (monoclonal antibodies, detected by Texas Red fluorescence) used to delineate myocyte boundaries and intercalated discs, and ‘blue’ for nuclei (methods as in Ref. [38]). FGFR1 localizes to the nucleus of cardiomyocytes (arrowheads). Sarcolemmal staining is also present but weak under these conditions. Strong FGFR1 staining can be seen in vascular cells. (B) Fluorescence staining with polyclonal anti-FGF-2 antibodies (methods as in Ref. [52]). FGF-2 localizes to the periphery and the nucleus of myocytes (arrowheads). It is also present in non-myocytes (arrows). Bar=50 µm.

 

   4. Concluding remarks
Top
 Abstract
 1. Introduction
 2. FGF-2
 3. FGF-2 in cardiac...
 4. Concluding remarks
References
 
Overall, there seems to be convincing evidence that FGF-2 plays an important role in compensatory hypertrophic growth in response to pressure overload in vivo. As suggested in this review, the mechanism by which FGF-2 is contributing to hypertrophy is likely to include combinations of major hypertrophic pathways described to-date, including those affecting fetal gene expression as well as protein and RNA synthesis. Irrespectively of the isoform(s) involved, and to the extent that cardiomyocyte growth per se, independently of fibrosis or other pathologies, is a contributing factor to the transition to decompensation and heart failure, the FGF-2-FGFR1 axis needs to be considered as a potential target for the management of hypertrophy. Antagonizing plasma membrane FGF-2-FGFR1 signaling may however be detrimental to the heart in view of the potent cardioprotective properties of FGF-2 [22,29,38]. Understanding FGF-2 isoform-specific signals and endpoints will require the study of translational regulation and nuclear versus plasma membrane mediated signaling, to selectively interfere with the accumulation and/or signal transduction of each isoform.


   Acknowledgements
 
This work was supported by grants from the Canadian Institutes for Health Research (CIHR) to EK and PAC. Z-SJ was supported by a postdoctoral fellowship from the CIHR/IMPACT program. SKJ was supported by a studentship from the Heart and Stroke Foundation of Canada.


   Notes
 
Time for primary review 27 days


   References
Top
 Abstract
 1. Introduction
 2. FGF-2
 3. FGF-2 in cardiac...
 4. Concluding remarks
 References
 

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