Fibroblast growth factor-2 and cardioprotection

Boosting myocardial resistance to acute as well as chronic ischemic damage would ameliorate the detrimental effects of numerous cardiac pathologies and reduce the probability of transition to heart failure. Experimental cardiology has pointed to ischemic and pharmacological pre- as well as post-conditioning as potent acute cardioprotective manipulations. Additional exciting experimental strategies include the induction of true regenerative and/or angiogenic responses to the damaged heart, resulting in sustained structural and functional beneficial effects. Fibroblast growth factor-2 (FGF-2), an endogenous multifunctional protein with strong affinity for the extracellular matrix and basal lamina and well-documented paracrine, autocrine and intacellular modes of action, has been shown over the years to exert acute and direct pro-survival effects, irrespectively of whether it is administered before, during or after an ischemic insult to the heart. FGF-2 is also a potent angiogenic protein and a crucial agent for the proliferation, expansion, and survival of several cell types including those with stem cell properties. Human clinical trials have pointed to a good safety record for this protein. In this review, we will present a case for the low molecular weight isoform of fibroblast growth factor-2 (lo-FGF-2) as a very promising therapeutic agent to achieve powerful acute as well as sustained benefits for the heart, due to its cytoprotective and regenerative properties.     

Fibroblast growth factor-9 is an endometrial stromal growth factor

Fibroblast growth factor-9 (FGF-9) is an autocrine/paracrine growth factor considered to be important for the growth and survival of motorneurons and prostate. In this study, we found that FGF-9 was expressed at high levels in normal uterine endometrium, especially during the late proliferative phase, which is coincident with the rise of estradiol and the time of uterine endometrial proliferation. Using quantitative RT-PCR analysis, we found that FGF-9 mRNA was expressed primarily by endometrial stromal cells. High affinity receptors of FGF-9 were detected in both epithelial and stromal cells but with distinct patterns. FGFR2IIIc and FGFR3IIIc are abundant in endometrial stromal cell. FGFR2IIIb is mostly expressed in endometrial epithelial cells, whereas FGFR3IIIb is found in both epithelial and stromal cells. Treatment with FGF-9 induces endometrial stromal proliferation in a dose-dependent manner. Expression of FGF-9 in stromal cells was induced by 17beta-estradiol but not by progesterone. Furthermore, the administration of 17beta-estradiol stimulates endometrial stromal cell proliferation and that can be inhibited by cotreatment with anti-FGF-9 antibody. Herein we demonstrate, for the first time, that FGF-9 is an autocrine estromedin endometrial stromal growth factor that plays roles in cyclic proliferation of uterine endometrial stroma.     

Fibroblast growth factor-2 is a sputum remodeling biomarker of severe asthma

Objective: Given the large phenotypic diversity of asthma, our aim was to characterize molecular profiles related to asthma severity using selected remodeling biomarkers in induced sputum. Methods: Induced sputum from healthy controls, patients with mild to moderate asthma and severe asthma were collected. Twelve selected biomarkers previously associated to airway remodeling such as connective tissue growth factor (CTGF), fibroblast growth factor (FGF)-2, matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, procollagen type 1 and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in sputum samples using ELISA or Luminex technology. FGF-2 level was also evaluated in bronchial biopsies using immunohistochemistry. Results: Sputum of severe asthma was characterized by reduced percentage of macrophages and increased percentage of neutrophils and eosinophils. FGF-2, MMP-1 and TIMP-1 levels increased with asthma severity. Interestingly, only FGF-2 level inversely correlated with FEV₁/FVC ratio. Although percentage of eosinophils correlated with asthma severity, it did not correlate with FGF-2 levels. Increased levels of FGF-2 with asthma severity were confirmed in bronchial biopsies by immunohistochemistry. Conclusions: Level of FGF-2 in induced sputum represents a relevant remodeling biomarker of asthma severity and significantly correlates with pulmonary function. FGF-2 sputum biomarker is proposed to reveal the phenotype of asthma characterized by fixed airflow obstruction.     

Fibroblast growth factor receptor-1 is expressed by endothelial progenitor cells

Recent experiments show that hematopoietic progenitor cell populations contain endothelial precursor cells. We have isolated a population of CD34(+) cells that expresses fibroblast growth factor receptor-1 (FGFR-1) and that differentiates into endothelial cells in vitro. We find that 4.5% +/- 2.1% of CD34(+) cells isolated from bone marrow, cord blood, and mobilized peripheral blood express FGFR-1 and that viable CD34(+)FGFR(+) cells are small, with little granularity, and express both primitive hematopoietic and endothelial markers on their surface. The primitive hematopoietic markers AC133, c-kit, and Thy-1 are coexpressed by 75%, 85%, and 64% of CD34(+)FGFR(+) cells, respectively. Most of the CD34(+)FGFR(+) cells also express antigens found on endothelial cells, such as CD31, vascular endothelial growth factor receptor-2, and the endothelial-specific cell surface marker, vascular endothelial cadherin (VE-cadherin), whereas 56% to 60% of the cells express Tie, Tek, and the endothelial-specific marker, P1H12. The CD34(+)FGFR(+) population is enriched in cells expressing endothelial-specific antigens compared with the CD34(+) population. Isolated CD34(+)FGFR(+) cells grow slowly in culture, are stimulated by fibroblast growth factor-2 and vascular endothelial growth factor, and give rise to cells that express von Willebrand factor and VE-cadherin and that incorporate acetylated low-density lipoprotein. These experiments show that FGFR-1 is expressed by a subpopulation of CD34(+) cells that give rise to endothelial cells in vitro, indicating that this population contains endothelial stem/progenitor cells.     

Fibroblast growth factor-2 stimulates endothelial nitric oxide synthase expression and inhibits apoptosis by a nitric oxide-dependent pathway in Nb2 lymphoma cells

We recently reported that the rat Nb2 T lymphoma cells expressed messenger RNAs (mRNAs) encoding both fibroblast growth factor-2 (FGF-2) and the FGF receptor, suggesting possible paracrine and/or autocrine roles for FGF-2 in lymphoma cell function. We have also shown that the Nb2 cells expressed endothelial nitric oxide synthase (eNOS) and produced low levels of nitric oxide (NO) that inhibited apoptosis of PRL-deprived cells via a PRL-independent, bcl-2-mediated pathway. In this study the effects of PRL and FGF-2 on Nb2 cell survival and NO production were further investigated. The percentages of nonapoptotic cells in PRL-treated vs. PRL-deprived cultures after 6 days were 95% and 53%, respectively. Addition of FGF-2 to PRL-deprived Nb2 cells did not stimulate cell proliferation, but the onset of apoptosis was significantly inhibited, such that more than 85% of the cells remained nonapoptotic after 6 days. The steady state levels of bcl-2 and bag-1 mRNAs were low in PRL-deprived Nb2 cells, but were markedly increased by PRL or FGF-2. bcl-2 expression was induced within 1 h of PRL or FGF-2 addition and continued to increase to a level 20- to 25-fold above the control level within 24 h. bag-1 expression also increased within 1 h after the addition of PRL or FGF-2, was maximal within 8 h, and declined slowly thereafter. The levels of eNOS mRNAs were low but detectable in growth-arrested Nb2 cells, and PRL further down-regulated eNOS mRNA levels over the next 24 h. In contrast, FGF-2 significantly increased eNOS mRNA levels within 2 h to reach a peak 10-fold induction by 12 h. FGF-2 stimulation of eNOS mRNA was accompanied by a 2- to 3.5-fold increase in cellular levels of the eNOS protein and a 2.5-fold increase in serine-phosphorylated eNOS. However, the ratio of serine-phosphorylated eNOS vs. total cellular eNOS was unchanged, indicating that FGF-2 did not affect the serine phosphorylation status of eNOS. Nb2 cells produced low basal levels of NO, which increased with increasing L-arginine concentrations. PRL did not further increase NO release in the presence of L-arginine (0.1 or 1 mM), but FGF-2 significantly (P: 相似文献   

成纤维细胞生长因子-21与糖尿病

成纤维细胞生长因子-21(FGF-21)是成纤维细胞家族成员之一,其受体可能为FGFR-1和FGFR-2,与受体的结合可能需要βKlotho,过氧化物酶体增殖物活化受体(PPAR)α对FGF-21的分泌起重要的调节作用.FGF-21可通过蛋白激酶B(Akt)信号转导途径抵抗细胞因子和糖脂毒性诱导的β细胞凋亡,通过非胰岛素信号依赖通路降低血糖,并且能改善脂代谢、刺激胰岛素分泌,且与PPARγ信号转导途径存在相互协同作用,显示出潜在的糖尿病治疗作用.     

Insulin-like growth factor-I stimulates oxytocin and progesterone production by bovine granulosa cells in culture

The effect of insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), fibroblast growth factor (FGF) and nerve growth factor (NGF) on production of oxytocin and progesterone by cultured bovine granulosa and luteal cells was studied. Secretion of oxytocin was stimulated, in a dose-dependent manner, by IGF-I at 48 and 120 h of culture to levels much higher than those after stimulation with LH, FSH, EGF, FGF or NGF. A similar effect of IGF-I was observed for progesterone but, in contrast to oxytocin, secretion of progesterone was not increased by EGF, NGF or FGF. During primary culture, for 4 h, of dispersed bovine luteal cells obtained from corpora lutea between days 4 and 10 of the oestrous cycle, all the growth factors tested failed to stimulate secretion of oxytocin or progesterone. The data suggest the relevance of growth factors (especially IGF-I) for ovarian physiology and their possible importance for differentiation of follicles and luteinization.     

Estradiol stimulates tyrosine phosphorylation of the insulin-like growth factor-1 receptor and insulin receptor substrate-1 in the uterus.

The signaling pathways associated with estrogen-induced proliferation of epithelial cells in the reproductive tract have not been defined. To identify receptor tyrosine kinases that are activated in vivo by 17 beta-estradiol (E2), uteri from ovariectomized mice were examined for enhanced tyrosine phosphorylation of various receptors and a receptor substrate following treatment with this hormone. Within 4 hr after hormone exposure, extracts showed increased phosphotyrosine (P-Tyr) immunoreactivity at several bands, including 170- and 180-kDa; these bands were still apparent at 24 hr after E2. Analysis of immunoprecipitates from uterine extracts revealed that E2 enhanced tyrosine phosphorylation of the insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor substrate-1 (IRS-1) by 6 hr. Comparison of supernatants from IRS-1 and control rabbit IgG immunoprecipitates indicated that the 170-kDa P-Tyr band in extracts was equivalent to IRS-1. The receptors for epidermal growth factor, platelet-derived growth factor, and basic fibroblast growth factor did not exhibit an E2-induced increase in P-Tyr content. The nonestrogenic steroid hormones examined did not stimulate the P-Tyr content of IGF-1R or IRS-1. Immunolocalization of P-Tyr and IRS-1 revealed strong reactivity in the epithelial layer of the uterus from E2-treated mice, suggesting that the majority of P-Tyr bands observed in immunoblots originate in the epithelium. Since hormonal activation of IRS-1 is epithelial, estrogen-specific, and initiated before maximal DNA synthesis occurs following treatment with hormone, this protein, as part of the IGF-1R pathway, may be important in mediating estrogen-stimulated proliferation in the uterus.     

Fibroblast growth factor-2 and epidermal growth factor modulate prolactin responses to TRH and dopamine in primary cultures

Fibroblast growth factor-2, (FGF-2) and epidermal growth factor (EGF) are expressed in most tissues of the organism including pituitary, FGF-2 increases PRL levels and PRL mRNA in GH3 cells and primary cultures, and it has been involved in the lactotroph proliferation and hyperplasia. EGF also increases PRL levels in vitro. However, the effects of these two factors in the responses of lactotroph cells to TRH and dopamine (DA) remain to be clarified. In the present work we have studied the modulator activity of FGF-2 and EGF on in vitro PRL in responses to TRH and DA in primary cultures from in vivo vehicle-or estrogen (E2)-treated rats. We have found that FGF-2 (2×10⁻¹¹ M) prevents the EGF-induced dose-dependent increase in PRL levels in control cells, and reversed the EGF-stimulating effects in cells from E2-treated rats. Both FGF-2 (2×10⁻¹¹ M) and EGF (6.6×10⁻⁹ M) significantly increase (>30% and >120%, respectively) the PRL levels in response to TRH (10⁻⁶ 10⁻⁵ M). FGF-2 blocked the inhibitory effects of low doses of DA (10⁻⁹ M). EGF was unable to do so, although markedly increased (>200%) the post-DA PRL rebound. In cells from in vivo E2-treated rats, FGF-2 increased (>50%) the PRL secretion in response to TRH, while EGF reduced responses to high doses of TRH (10⁻⁶, 10⁻⁵ M). In addition, FGF-2 reversed and EGF increased the inhibitory effects of DA. Both FGF-2 and EGF completely blocked the post-DA PRL rebound, in these cells. Taken together our data suggest that FGF-2 and EGF are important regulators of lactotroph responsiveness to TRH and DA in vitro, although their actions are highly dependent on estrogenic milieu.     

Fibroblast growth factor-2 induces recovery of pulmonary blood flow in canine emphysema models

STUDY OBJECTIVES: Fibroblast growth factor (FGF)-2 is one of the most powerful angiogenic growth factors to be evaluated as an agent for the promotion of angiogenesis. The aim of this study is to investigate whether intratracheal administration of controlled-release FGF-2 microspheres restores pulmonary function in beagle dogs with emphysema. DESIGN: Randomized, controlled, experimental animal study. SUBJECTS: Eighteen Wister rats and 15 adult beagle dogs. METHODS: In the rat study, we compared the time profiles of the radioactivity remaining after intratracheal injection of 125I-labeled FGF-2, either incorporated with the controlled-release microspheres or as an aqueous solution. In the dog study, elastase-induced emphysema models were developed in 10 animals, classified into the following three groups: control group (n = 5), emphysema model with empty microspheres-treated group (FGF - group, n = 5), and emphysema model with FGF-2 containing microspheres-treated group (FGF + group, n = 5). RESULTS: In the rat study, controlled-release microspheres maintained higher whole-lung FGF-2 concentrations after intratracheal administration. In the dog study, Pa(O2) in the FGF + group was significantly higher than in the FGF - group after treatment. Pulmonary perfusion dynamic MRI revealed significant improvement in the signal intensity of damaged lung with the FGF + group. Linear intercept of the FGF + group was significantly reduced than the FGF - group. CONCLUSION: Results indicate that intratracheal administration of FGF-2 induced an increase in pulmonary blood flow in the damaged lung and led to recovery of pulmonary function. The controlled-release microsphere system increased the effectiveness of FGF-2.     

The type 2 iodothyronine deiodinase is expressed in the rat uterus and induced during pregnancy

Thyroid hormones are of considerable importance for vertebrate reproductive function and during development. To further assess the role of these compounds in this capacity, we examined the expression pattern of the type 2 iodothyronine deiodinase (D2), which converts T(4) to the more active hormone T(3), in the rat uterus in both the nonpregnant and the pregnant state. D2 activity was identified as the predominant, if not only, 5'-deiodinase in the nonpregnant rat uterus. The expression of D2 messenger RNA was located by in situ hybridization to the endometrial stromal cells, where the signal was particularly enriched in the region adjacent to the epithelial cells of the uterine lumen. During pregnancy, D2 activity increased, peaking on day 17 of gestation (embryonic day 17). At that time, uterine D2 activity exceeded that in the placenta, as well as that in the fetal tissues. In the earlier stages of pregnancy before placental formation (e.g. embryonic days 10-11), D2 messenger RNA in the rat uterus was located outside the decidual tissue, which was observed, as in previous studies, to highly express the inactivating type 3 deiodinase. In summary, the rat uterus, particularly during pregnancy, seems to be a site of active thyroid hormone metabolism, presumably designed to maintain the optimal thyroid hormone environment for both the fetus and the maternal uterine tissue.     

Phorbol ester stimulates progesterone production by isolated bovine luteal cells

The tumor promoter, phorbol 12-myristate-13-acetate (PMA), is known to modulate the response of several steroidogenic tissues presumably by activating a Ca++- and phospholipid-dependent protein kinase (protein kinase C). The presence of this kinase has been demonstrated in bovine corpus luteum, although its role in steroidogenesis by these cells is unknown. We report here the effects of PMA on progesterone production by the enzymically dispersed bovine luteal cells in vitro. PMA (1-50 nM) produced a dose- and time-related increase in progesterone production by the luteal cells. The maximum stimulation was achieved with 10 nM PMA. Higher concentrations of PMA led to a decline of steroidogenesis close to the basal level. A nonpromoting derivative, 4 alpha-phorbol 12,13-didecanoate had no effect. The PMA-induced stimulation of progesterone production was not associated with a change in the cAMP level. PMA added together with suboptimal doses of human CG, 8Br-cAMP, cholera toxin, or forskolin significantly increased the amount of progesterone produced. PMA as well as human CG-induced steroidogenesis was sensitive to cycloheximide inhibition. The conversion of exogenous pregnenolone or 25-hydroxycholesterol to progesterone was not altered by PMA. We conclude that PMA at nanomolar concentrations is able to stimulate progesterone production by bovine luteal cells and that the site of action of PMA is distal to the formation of cAMP but before the formation of pregnenolone. The observed effects of PMA in luteal cells are probably linked to its ability to activate protein kinase C, since a diacylglycerol could mimic the steroidogenic action of PMA.